Pyridone and aza-pyridone compounds and methods of use

ABSTRACT

Pyridone and aza-pyridone compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This non-provisional application filed under 37 CFR § 1.53(b), claimsthe benefit under 35 USC § 119(e) of U.S. Provisional Application Ser.No. 61/443,952 filed on 17 Feb. 2011, and U.S. Provisional ApplicationSer. No. 61/332,353 filed on 7 May 2010, which are incorporated byreference in entirety

FIELD OF THE INVENTION

The invention relates generally to compounds for treating disordersmediated by Bruton's Tyrosine Kinase (Btk) including inflammation,immunological, and cancer, and more specifically to compounds whichinhibit Btk activity. The invention also relates to methods of using thecompounds for in vitro, in situ, and in vivo diagnosis or treatment ofmammalian cells, or associated pathological conditions.

BACKGROUND OF THE INVENTION

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Bruton's Tyrosine Kinase (Btk) is a member of the Tecfamily of tyrosine kinases, and is a regulator of early B-celldevelopment as well as mature B-cell activation, signaling, andsurvival.

B-cell signaling through the B-cell receptor (BCR) can lead to a widerange of biological outputs, which in turn depend on the developmentalstage of the B-cell. The magnitude and duration of BCR signals must beprecisely regulated. Aberrant BCR-mediated signaling can causedisregulated B-cell activation and/or the formation of pathogenicauto-antibodies leading to multiple autoimmune and/or inflammatorydiseases. Mutation of Btk in humans results in X-linkedagammaglobulinaemia (XLA). This disease is associated with the impairedmaturation of B-cells, diminished immunoglobulin production, compromisedT-cell-independent immune responses and marked attenuation of thesustained calcium sign upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmunedisease and/or inflammatory disease has been established inBtk-deficient mouse models. For example, in standard murine preclinicalmodels of systemic lupus erythematosus (SLE), Btk deficiency has beenshown to result in a marked amelioration of disease progression.Moreover, Btk deficient mice can also be resistant to developingcollagen-induced arthritis and can be less susceptible toStaphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoralimmune system in the pathogenesis of autoimmune and/or inflammatorydiseases. Protein-based therapeutics (such as Rituxan) developed todeplete B-cells, represent an approach to the treatment of a number ofautoimmune and/or inflammatory diseases. Because of Btk's role in B-cellactivation, inhibitors of Btk can be useful as inhibitors of B-cellmediated pathogenic activity (such as autoantibody production).

Btk is also expressed in osteoclasts, mast cells and monocytes and hasbeen shown to be important for the function of these cells. For example,Btk deficiency in mice is associated with impaired IgE-mediated mastcell activation (marked diminution of TNF-alpha and other inflammatorycytokine release), and Btk deficiency in humans is associated withgreatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment ofallergic disorders and/or autoimmune and/or inflammatory diseases suchas: SLE, rheumatoid arthritis, multiple vasculitides, idiopathicthrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis,and asthma. In addition, Btk has been reported to play a role inapoptosis; thus, inhibition of Btk activity can be useful for cancer, aswell as the treatment of B-cell lymphoma and leukemia. Moreover, giventhe role of Btk in osteoclast function, the inhibition of Btk activitycan be useful for the treatment of bone disorders such as osteoporosis.

SUMMARY OF THE INVENTION

The invention relates generally to Formula I compounds with Bruton'sTyrosine Kinase (Btk) modulating activity.

Formula I compounds have the structures:

including stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof. The various substituents are defined herein below.

One aspect of the invention is a pharmaceutical composition comprised ofa Formula I compound and a pharmaceutically acceptable carrier, glidant,diluent, or excipient. The pharmaceutical composition may furthercomprise a second therapeutic agent.

Another aspect of the invention is a process for making a pharmaceuticalcomposition which comprises combining a Formula I compound with apharmaceutically acceptable carrier.

The invention includes a method of treating a disease or disorder whichmethod comprises administering a therapeutically effective amount of aFormula I compound to a patient with a disease or disorder selected fromimmune disorders, cancer, cardiovascular disease, viral infection,inflammation, metabolism/endocrine function disorders and neurologicaldisorders, and mediated by Bruton's tyrosine kinase.

The invention includes a kit for treating a condition mediated byBruton's tyrosine kinase, comprising: a) a first pharmaceuticalcomposition comprising a Formula I compound; and b) instructions foruse.

The invention includes a Formula I compound for use as a medicament, andfor use in treating a disease or disorder selected from immunedisorders, cancer, cardiovascular disease, viral infection,inflammation, metabolism/endocrine function disorders and neurologicaldisorders, and mediated by Bruton's tyrosine kinase.

The invention includes use of a Formula I compound in the manufacture ofa medicament for the treatment of immune disorders, cancer,cardiovascular disease, viral infection, inflammation,metabolism/endocrine function disorders and neurological disorders, andwhere the medicament mediates Bruton's tyrosine kinase.

The invention includes methods of making a Formula I compound.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an exemplary synthetic route to prepare 6-chloro,4-aminopyridazinone compounds, including6-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one101f, from 3-nitropyrazole-5-carboxylic acid.

FIG. 2 shows an exemplary synthetic route to a tricyclic amide-phenylboronate compounds, including2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one101m, from 4,5,6,7-tetrahydro-1H-indole.

FIG. 3 shows an exemplary synthetic route to tricyclic amide-phenylbromide compounds, including2-bromo-6-(1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzylacetate 104h, from 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylicacid.

FIG. 4 shows another exemplary synthetic route to tricyclic amide-phenylbromide compounds, including6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-one105i, from 3-methylcyclopent-2-enone.

FIG. 5 shows an exemplary synthetic route to tricyclic1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-onecompounds as boronate esters, including2-(1-Oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylAcetate 118f from 5,6,7,8-tetrahydroindolizine-2-carboxylic acid.

FIG. 6 shows an exemplary synthetic route to intermediate2-Bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 198d from 1,3-dibromo-5-fluoro-2-iodobenzene.

FIG. 7 shows an exemplary synthetic route to intermediate4-Fluoro-2-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 198g.

FIG. 8 shows an exemplary synthetic route to intermediate5-Fluoro-2-(1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 210e.

FIG. 9 shows an exemplary synthetic route to intermediate5-[5-fluoro-2-(acetoxymethyl)-3-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one212c.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.

Definitions

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms (C₁-C₁₂), wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. In anotherembodiment, an alkyl radical is one to eight carbon atoms (C₁-C₈), orone to six carbon atoms (C₁-C₆). Examples of alkyl groups include, butare not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl(n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂),1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu,i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term “alkylene” as used herein refers to a saturated linear orbranched-chain divalent hydrocarbon radical of one to twelve carbonatoms (C₁-C₁₂), wherein the alkylene radical may be optionallysubstituted independently with one or more substituents described below.In another embodiment, an alkylene radical is one to eight carbon atoms(C₁-C₈), or one to six carbon atoms (C₁-C₆). Examples of alkylene groupsinclude, but are not limited to, methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), and the like.

The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and“cycloalkyl” refer to a monovalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms (C₃-C₁₂) as a monocyclicring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycleshaving 7 to 12 atoms can be arranged, for example, as a bicyclo[4,5],[5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10ring atoms can be arranged as a bicyclo[5,6] or [6,6] system, or asbridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms (C₆-C₂₀) derived by the removal of one hydrogen atom from a singlecarbon atom of a parent aromatic ring system. Some aryl groups arerepresented in the exemplary structures as “Ar”. Aryl includes bicyclicradicals comprising an aromatic ring fused to a saturated, partiallyunsaturated ring, or aromatic carbocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, biphenyl, indenyl,indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and thelike. Aryl groups are optionally substituted independently with one ormore substituents described herein.

“Arylene” means a divalent aromatic hydrocarbon radical of 6-20 carbonatoms (C₆-C₂₀) derived by the removal of two hydrogen atom from a twocarbon atoms of a parent aromatic ring system. Some arylene groups arerepresented in the exemplary structures as “Ar”. Arylene includesbicyclic radicals comprising an aromatic ring fused to a saturated,partially unsaturated ring, or aromatic carbocyclic ring. Typicalarylene groups include, but are not limited to, radicals derived frombenzene (phenylene), substituted benzenes, naphthalene, anthracene,biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene,1,2,3,4-tetrahydronaphthyl, and the like. Arylene groups are optionallysubstituted

The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double and/or triple bonds withinthe ring) carbocyclic radical of 3 to about 20 ring atoms in which atleast one ring atom is a heteroatom selected from nitrogen, oxygen,phosphorus, sulfur, and silicon, the remaining ring atoms being C, whereone or more ring atoms is optionally substituted independently with oneor more substituents described below. A heterocycle may be a monocyclehaving 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatomsselected from N, O, P, and S) or a bicycle having 7 to 10 ring members(4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, andS), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system.Heterocycles are described in Paquette, Leo A.; “Principles of ModernHeterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularlyChapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds,A series of Monographs” (John Wiley & Sons, New York, 1950 to present),in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc.(1960) 82:5566. “Heterocyclyl” also includes radicals where heterocycleradicals are fused with a saturated, partially unsaturated ring, oraromatic carbocyclic or heterocyclic ring. Examples of heterocyclicrings include, but are not limited to, morpholin-4-yl, piperidin-1-yl,piperidonyl, oxopiperazinyl, piperazinyl, piperazin-4-yl-2-one,piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl,S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidin-1-yl,octahydropyrido[1,2-a]pyrazin-2-yl, [1,4]diazepan-1-yl, pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pyridyl ureas. Spiro moieties are also includedwithin the scope of this definition. Examples of a heterocyclic groupwherein 2 ring atoms are substituted with oxo (═O) moieties arepyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groupsherein are optionally substituted independently with one or moresubstituents described herein.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings, and includes fused ring systems (at least one ofwhich is aromatic) of 5-20 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, for example,2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl(including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups areoptionally substituted independently with one or more substituentsdescribed herein.

The heterocycle or heteroaryl groups may be carbon (carbon-linked), ornitrogen (nitrogen-linked) bonded where such is possible. By way ofexample and not limitation, carbon bonded heterocycles or heteroarylsare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline.

The terms “treat” and “treatment” refer to therapeutic treatment,wherein the object is to slow down (lessen) an undesired physiologicalchange or disorder, such as the development or spread of arthritis orcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those with the conditionor disorder.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats the particulardisease, condition, or disorder, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease, condition, ordisorder, or (iii) prevents or delays the onset of one or more symptomsof the particular disease, condition, or disorder described herein. Inthe case of cancer, the therapeutically effective amount of the drug mayreduce the number of cancer cells; reduce the tumor size; inhibit (i.e.,slow to some extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., slow to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; and/orrelieve to some extent one or more of the symptoms associated with thecancer. To the extent the drug may prevent growth and/or kill existingcancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy,efficacy can be measured, for example, by assessing the time to diseaseprogression (TTP) and/or determining the response rate (RR).

“Inflammatory disorder” as used herein can refer to any disease,disorder, or syndrome in which an excessive or unregulated inflammatoryresponse leads to excessive inflammatory symptoms, host tissue damage,or loss of tissue function “Inflammatory disorder” also refers to apathological state mediated by influx of leukocytes and/or neutrophilchemotaxis.

“Inflammation” as used herein refers to a localized, protective responseelicited by injury or destruction of tissues, which serves to destroy,dilute, or wall off (sequester) both the injurious agent and the injuredtissue Inflammation is notably associated with influx of leukocytesand/or neutrophil chemotaxis Inflammation can result from infection withpathogenic organisms and viruses and from noninfectious means such astrauma or reperfusion following myocardial infarction or stroke, immuneresponse to foreign antigen, and autoimmune responses. Accordingly,inflammatory disorders amenable to treatment with Formula I compoundsencompass disorders associated with reactions of the specific defensesystem as well as with reactions of the nonspecific defense system.

“Specific defense system” refers to the component of the immune systemthat reacts to the presence of specific antigens. Examples ofinflammation resulting from a response of the specific defense systeminclude the classical response to foreign antigens, autoimmune diseases,and delayed type hypersensitivity response mediated by T-cells. Chronicinflammatory diseases, the rejection of solid transplanted tissue andorgans, e.g., kidney and bone marrow transplants, and graft versus hostdisease (GVHD), are further examples of inflammatory reactions of thespecific defense system.

The term “nonspecific defense system” as used herein refers toinflammatory disorders that are mediated by leukocytes that areincapable of immunological memory (e.g., granulocytes, and macrophages).Examples of inflammation that result, at least in part, from a reactionof the nonspecific defense system include inflammation associated withconditions such as adult (acute) respiratory distress syndrome (ARDS) ormultiple organ injury syndromes; reperfusion injury; acuteglomerulonephritis; reactive arthritis; dermatoses with acuteinflammatory components; acute purulent meningitis or other centralnervous system inflammatory disorders such as stroke; thermal injury;inflammatory bowel disease; granulocyte transfusion associatedsyndromes; and cytokine-induced toxicity.

“Autoimmune disease” as used herein refers to any group of disorders inwhich tissue injury is associated with humoral or cell-mediatedresponses to the body's own constituents.

“Allergic disease” as used herein refers to any symptoms, tissue damage,or loss of tissue function resulting from allergy. “Arthritic disease”as used herein refers to any disease that is characterized byinflammatory lesions of the joints attributable to a variety ofetiologies. “Dermatitis” as used herein refers to any of a large familyof diseases of the skin that are characterized by inflammation of theskin attributable to a variety of etiologies. “Transplant rejection” asused herein refers to any immune reaction directed against graftedtissue, such as organs or cells (e.g., bone marrow), characterized by aloss of function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia. The therapeutic methods of thepresent invention include methods for the treatment of disordersassociated with inflammatory cell activation.

“Inflammatory cell activation” refers to the induction by a stimulus(including, but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including, but not limited to,major histocompatability antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclearleukocytes such as neutrophils, basophils, and eosinophils), mast cells,dendritic cells, Langerhans cells, and endothelial cells). It will beappreciated by persons skilled in the art that the activation of one ora combination of these phenotypes in these cells can contribute to theinitiation, perpetuation, or exacerbation of an inflammatory disorder.

The term “NSAID” is an acronym for “non-steroidal anti-inflammatorydrug” and is a therapeutic agent with analgesic, antipyretic (loweringan elevated body temperature and relieving pain without impairingconsciousness) and, in higher doses, with anti-inflammatory effects(reducing inflammation). The term “non-steroidal” is used to distinguishthese drugs from steroids, which (among a broad range of other effects)have a similar eicosanoid-depressing, anti-inflammatory action. Asanalgesics, NSAIDs are unusual in that they are non-narcotic. NSAIDsinclude aspirin, ibuprofen, and naproxen. NSAIDs are usually indicatedfor the treatment of acute or chronic conditions where pain andinflammation are present. NSAIDs are generally indicated for thesymptomatic relief of the following conditions: rheumatoid arthritis,osteoarthritis, inflammatory arthropathies (e.g. ankylosing spondylitis,psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea,metastatic bone pain, headache and migraine, postoperative pain,mild-to-moderate pain due to inflammation and tissue injury, pyrexia,ileus, and renal colic. Most NSAIDs act as non-selective inhibitors ofthe enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1)and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyzes theformation of prostaglandins and thromboxane from arachidonic acid(itself derived from the cellular phospholipid bilayer by phospholipaseA₂). Prostaglandins act (among other things) as messenger molecules inthe process of inflammation. COX-2 inhibitors include celecoxib,etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, andvaldecoxib.

The terms “cancer” refers to or describe the physiological condition inmammals that is typically characterized by unregulated cell growth. A“tumor” comprises one or more cancerous cells. Examples of cancerinclude, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma,and leukemia or lymphoid malignancies. More particular examples of suchcancers include squamous cell cancer (e.g., epithelial squamous cellcancer), lung cancer including small-cell lung cancer, non-small celllung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinomaof the lung, cancer of the peritoneum, hepatocellular cancer, gastric orstomach cancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectalcancer, endometrial or uterine carcinoma, salivary gland carcinoma,kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer,hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head andneck cancer.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer, regardless of mechanism of action. Classes ofchemotherapeutic agents include, but are not limited to: alkylatingagents, antimetabolites, spindle poison plant alkaloids,cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies,photosensitizers, and kinase inhibitors. Chemotherapeutic agents includecompounds used in “targeted therapy” and conventional chemotherapy.Examples of chemotherapeutic agents include: erlotinib (TARCEVA®,Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU(fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®,Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin(cis-diamine, dichloroplatinum(II), CAS No. 15663-27-1), carboplatin(CAS No. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology,Princeton, N.J.), trastuzumab (HERCEPTIN®, Genentech), temozolomide(4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide,CAS No. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine,NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1/2,HPPD, and rapamycin.

More examples of chemotherapeutic agents include: oxaliplatin(ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent(SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin(folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib(TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs),gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11,Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE®(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.),vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chloranmbucil, AG1478,AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib(GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa andcyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, calicheamicin gamma1I, calicheamicin omegaI1 (Angew Chem.Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A;bisphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores), aclacinomysins, actinomycin, authramycin,azaserine, bleomycins, cactinomycin, carabicin, carminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin,marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine; vinorelbine (NAVELBINE®)); novantrone; teniposide;edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche);ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid; andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipidkinase inhibitors; (vi) antisense oligonucleotides, particularly thosewhich inhibit expression of genes in signaling pathways implicated inaberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, suchas oblimersen (GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; topoisomerase 1 inhibitorssuch as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptablesalts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” aretherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (OMNITARG™, 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), tositumomab (Bexxar, Corixia), and the antibody drugconjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

Humanized monoclonal antibodies with therapeutic potential aschemotherapeutic agents in combination with the Btk inhibitors of theinvention include: alemtuzumab, apolizumab, aselizumab, atlizumab,bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumabmertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab,daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab,fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab,labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab,motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab,ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab,pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab,sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab,urtoxazumab, and visilizumab.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds of theinvention, including compounds produced by a process comprisingcontacting a Formula I compound of this invention with a mammal for aperiod of time sufficient to yield a metabolic product thereof.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or l meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity. In one aspect, a stereoisomer of this invention can bepresent in predominant form, e.g. greater than 50% ee (enantiomericexcess), greater than 80% ee, greater than 90% ee, greater than 95% ee,or greater than 99% ee.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The term “diastereomer” refers to stereoisomeric molecules which are notenantiomers. Diastereomers include cis-trans isomers and conformationalisomers which have the same molecular formula but which have a differentgeometric structure.

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis(2-hydroxy-3-naphthoate)) salts. A pharmaceuticallyacceptable salt may involve the inclusion of another molecule such as anacetate ion, a succinate ion or other counter ion. The counter ion maybe any organic or inorganic moiety that stabilizes the charge on theparent compound. Furthermore, a pharmaceutically acceptable salt mayhave more than one charged atom in its structure. Instances wheremultiple charged atoms are part of the pharmaceutically acceptable saltcan have multiple counter ions. Hence, a pharmaceutically acceptablesalt can have one or more charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,methanesulfonic acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, trifluoroacetic acid, maleic acid, succinicacid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalicacid, glycolic acid, salicylic acid, a pyranosidyl acid, such asglucuronic acid or galacturonic acid, an alpha hydroxy acid, such ascitric acid or tartaric acid, an amino acid, such as aspartic acid orglutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid,a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid,or the like.

If the compound of the invention is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include, but are not limited to, organicsalts derived from amino acids, such as glycine and arginine, ammonia,primary, secondary, and tertiary amines, and cyclic amines, such aspiperidine, morpholine and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum and lithium.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine.

The terms “compound of this invention,” and “compounds of the presentinvention” include compounds of Formulas I and stereoisomers, tautomers,solvates, metabolites, and pharmaceutically acceptable salts andprodrugs thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent hydrates, solvates, and polymorphs of suchcompounds, and mixtures thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent unlabeled forms as well as isotopicallylabeled forms of the compounds. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as, but not limited to 2H(deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S,36Cl, and 125I. Various isotopically labeled compounds of the presentinvention, for example those into which radioactive isotopes such as 3H,13C, and 14C are incorporated. Such isotopically labelled compounds maybe useful in metabolic studies, reaction kinetic studies, detection orimaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. Deuterium labelled or substituted therapeutic compounds of theinvention may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism, and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements. An18F labeled compound may be useful for PET or SPECT studies.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. Further, substitution with heavierisotopes, particularly deuterium (i.e., 2H or D) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements or animprovement in therapeutic index. It is understood that deuterium inthis context is regarded as a substituent in the compound of the formula(I). The concentration of such a heavier isotope, specificallydeuterium, may be defined by an isotopic enrichment factor. In thecompounds of this invention any atom not specifically designated as aparticular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Accordingly, inthe compounds of this invention any atom specifically designated as adeuterium (D) is meant to represent deuterium.

Pyridone and Aza-Pyridone Compounds

The present invention provides pyridone and aza-pyridone compounds ofFormula I, including Formulas Ia-bf, and pharmaceutical formulationsthereof, which are potentially useful in the treatment of diseases,conditions and/or disorders modulated by Btk kinase

including stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein:

R¹ is H, D, F, Cl, CN, —NH₂, —NHCH₃, —N(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃,—OCH₂CH₂OH, heteroaryl selected from imidazolyl and pyrazolyl,heterocyclyl selected from oxetanyl and azetidinyl, and C₁-C₃ alkyl;

R², R³ and R⁴ are independently selected from H, D, F, Cl, —NH₂, —NHCH₃,—N(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, and C₁-C₃ alkyl;

R⁵ is optionally substituted C₆-C₂₀ aryl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₁-C₂₀ heteroaryl, —(C₆-C₂₀ aryl)-(C₂-C₂₀ heterocyclyl),—(C₁-C₂₀ heteroaryl)-(C₂-C₂₀ heterocyclyl), —(C₁-C₂₀ heteroaryl)-(C₁-C₆alkyl), or —(C₁-C₂₀ heteroaryl)-C(═O)—(C₂-C₂₀ heterocyclyl);

R⁶ is H, F, —NH₂, —OH, or optionally substituted C₁-C₃ alkyl;

X is S, S(═O), S(═O)₂, N, NR⁶, O, or CR⁷;

R⁷ is independently selected from H, D, F, Cl, —CH₃, —CH₂CH₃, —CN,—CH₂F, —CHF₂, —CF₃, —NH₂, —OH, and —OCH₃;

Y¹ and Y² are independently selected from CR⁶ and N;

Z¹, Z², Z³, and Z⁴ are independently selected from C, CR⁷, and N;

Z⁵ is selected from —C(R³)₂—, —C(═O)—, —N(R⁶)—, —C(R³)₂C(R³)₂—,—C(R³)₂C(═O)—, —CR³═CR³—, —CR³═N—, —N(R⁶)C(R³)₂—, —N(R⁶)C(R³)₂C(R³)₂—,and —OC(R³)₂C(R³)₂—;

one of Z¹ and Z², or X and Z¹, where X is not S, S(═O), or S(═O)₂, formsa five-, six-, or seven-membered aryl, carbocyclyl, heterocyclyl orheteroaryl ring;

where alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl areoptionally substituted with one or more groups independently selectedfrom D, F, Cl, Br, I, —CH₃, —CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH,—C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CH₂OP(O)(OH)₂, —CN, —CH₂F, —CHF₂, —CF₃, —CO₂H, —COCH₃, —CO₂CH₃,—CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃, —CON(CH₃)₂, —C(CH₃)₂CONH₂,—NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃,—N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, ═O, —OH, —OCH₃,—OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃, —CH₂OCH₃, —S(O)₂CH₃,cyclopropyl, azetidinyl, 1-methylazetidin-3-yl)oxy,N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, oxetanyl, andmorpholino.

In one aspect, Formula I compounds are 3-amino-5-phenylpyridine-2(1H)-one Ia where Y¹ and Y² are CR⁶, 4-amino-6-phenylpyridazin-3(2H)-one Ib where Y¹ is N and Y² is CR⁶, and 3-amino-5-phenylpyrazin-2(1H)-ones Ic where Y¹ is CR⁶ and Y² is N.

Exemplary embodiments of Formula I compounds include compounds ofFormulas Ia-Ibf:

Exemplary embodiments of Formula I compounds include where the group:

forms the structures:

where the wavy line indicates the site of attachment.

Exemplary embodiments of Formula I compounds include wherein the centerphenyl ring group is substituted or not substituted such as: (i) R¹, R²,R³, and R⁴ are each H; (ii) or one or more of R¹, R², R³, and R⁴ are F;(iii) R¹ is selected from F, —CH₃, —CH₂F, —CHF₂, and —CF₃; (iv) R¹ is—CH₂OH; (v) R³ is F; and (vi) R¹ is —CH₂OH, R² and R⁴ are each H, and R³is F.

Exemplary embodiments of Formula I compounds include wherein R⁵ isoptionally substituted C₆-C₂₀ aryl selected from phenyl and naphthyl.

Exemplary embodiments of Formula I compounds include wherein R⁵ isoptionally substituted C₃-C₁₂ carbocyclyl selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

Exemplary embodiments of Formula I compounds include wherein R⁵ isoptionally substituted C₂-C₂₀ heterocyclyl selected from oxetanyl,azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl,morpholinyl, and tetrahydropyranyl.

Exemplary embodiments of Formula I compounds include wherein R⁵ isoptionally substituted C₁-C₂₀ heteroaryl selected from pyrazolyl,pyridinyl, pyrimidinyl,5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl,5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl,6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl, and1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridine-2-yl.

Exemplary embodiments of Formula I compounds include wherein R⁵ isselected from the structures:

where the wavy line indicates the site of attachment.

Exemplary embodiments of Formula I compounds include wherein R⁶ is H.

Exemplary embodiments of Formula I compounds include wherein Y¹ is CR⁶and Y² is N.

Exemplary embodiments of Formula I compounds include wherein Y¹ is N andY² is CR⁶.

Exemplary embodiments of Formula I compounds include wherein Y¹ and Y²are each CR⁶.

Each solid/dashed line,

, in the five-membered ring formed by X, Z¹, Z², Z³, and Z⁴ in thestructures of Formula I compounds represents a single bond or a doublebond, with the proviso that any two double bonds in the ring are notadjacent.

The Formula I compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention.

In addition, the present invention embraces all diastereomers, includingcis-trans (geometric) and conformational isomers. For example, if aFormula I compound incorporates a double bond or a fused ring, the cis-and trans-forms, as well as mixtures thereof, are embraced within thescope of the invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms.

The compounds of the present invention may also exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

Biological Evaluation

The relative efficacies of Formula I compounds as inhibitors of anenzyme activity (or other biological activity) can be established bydetermining the concentrations at which each compound inhibits theactivity to a predefined extent and then comparing the results.Typically, the preferred determination is the concentration thatinhibits 50% of the activity in a biochemical assay, i.e., the 50%inhibitory concentration or “IC₅₀”. Determination of IC₅₀ values can beaccomplished using conventional techniques known in the art. In general,an IC₅₀ can be determined by measuring the activity of a given enzyme inthe presence of a range of concentrations of the inhibitor under study.The experimentally obtained values of enzyme activity then are plottedagainst the inhibitor concentrations used. The concentration of theinhibitor that shows 50% enzyme activity (as compared to the activity inthe absence of any inhibitor) is taken as the IC₅₀ value. Analogously,other inhibitory concentrations can be defined through appropriatedeterminations of activity. For example, in some settings it can bedesirable to establish a 90% inhibitory concentration, i.e., IC₉₀, etc.

Formula I compounds were tested by a standard biochemical Btk KinaseAssay (Example 901).

A general procedure for a standard cellular Btk Kinase Assay that can beused to test Formula I compounds is a Ramos Cell Btk Assay (Example902).

A standard cellular B-cell proliferation assay can be used to testFormula I compounds with B-cells purified from spleen of Balb/c mice(Example 903).

A standard T cell proliferation assay can be used to test Formula Icompounds with T-cells purified from spleen of Balb/c mice (Example904).

A CD86 Inhibition assay can be conducted on Formula I compounds for theinhibition of B cell activity using total mouse splenocytes purifiedfrom spleens of 8-16 week old Balb/c mice (Example 905).

A B-ALL Cell Survival Assay can be conducted on Formula I compounds tomeasure the number of viable B-ALL cells in culture (Example 906).

A CD69 Whole Blood Assay can be conducted on Formula I compounds todetermine the ability of compounds to inhibit the production of CD69 byB lymphocytes in human whole blood activated by crosslinking surface IgMwith goat F(ab′)2 anti-human IgM (Example 907).

Exemplary Formula I compounds in Tables 1, 2, and 3 were made,characterized, and tested for inhibition of Btk according to the methodsof this invention, and have the following structures and correspondingnames (ChemDraw Ultra, Version 9.0.1, and ChemBioDraw, Version 11.0,CambridgeSoft Corp., Cambridge Mass.). Where more than one name isassociated with a Formula I compound or intermediate, the chemicalstructure shall define the compound.

TABLE 1 Btk M + H IC₅₀ No. Structure Name m/z (μMol) 101

2-(2-methyl-3-(5-(5-methyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo- 1,6-dihydropyridazin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 525.20.002 102

2-(2-methyl-3-(5-(5-methyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo- 1,6-dihydropyridazin-3- yl)phenyl)-3,4-dihydropyrazino[1,2-a]indol- 1(2H)-one 521.2 0.0229 103

4-{2-Methyl-3-[1-methyl-5- ({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl}amino)-6-oxo-1,6- dihydropyridazin-3-yl]phenyl}-7-thia-4- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6),9,11-tetraen-5-one 538.2 3.2 104

5-[2-(Hydroxymethyl)-3-[1- methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 514.2 0.00087105

10-[2-(Hydroxymethyl)-3-[1- methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl]phenyl]-4,4-dimethyl-7- thia-10-azatricyclo[6.4.0.02,6]dodeca- 1(8),2(6)-dien-9-one 528.2 0.010 106

2-(3-(5-(5-cyclopropyl-1H- pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3- yl)-2- (hydroxymethyl)phenyl)- 3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-1(2H)-one 525 0.0010 107

2-(2-(hydroxymethyl)-3-(1- methyl-5-(5- morpholinopyridin-2-ylamino)-6-oxo-1,6- dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-1(2H)-one 581 0.0101 108

2-(3-(5-(5-acetyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1- methyl-6-oxo-1,6- dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)- 3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 582.3 0.0061 109

2-(2-(hydroxymethyl)-3-(1- methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-1(2H)-one 497.2 0.0062 110

2-(3-(5-(6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)- 3,4,6,7,8.9- hexahydropyrazino[1,2-a]indol-1(2H)-one 541.4 0.0077 111

5-[2-(Hydroxymethyl)-3-[4- methyl-5-oxo-6-(pyridine-3-ylamino)-4,5-dihydropyrazin- 2-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.02,7]trideca- 1(9),2(7)-dien-6-one 514.2 112

2-(2-(hydroxymethyl)-3-(1- methyl-5-(5-methyl-1H-pyrazol-3-ylamino)-6-oxo- 1,6-dihydropyridin-3- yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-1(2H)-one 499.3 113

2-(2-(hydroxymethyl)-3-(1- methyl-5-(5-(4- methylpiperazin-1-yl)pyridine-2-ylamino)-6- oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 594.30.005 114

2-(3-(6-(1-cyclopropyl-1H- pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2- yl)-2- (hydroxymethyl)phenyl)- 3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-1(2H)-one 526.3 115

5-[5-Fluoro-2- (hydroxymethyl)-3-[1- methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.02,7]trideca- 1(9),2(7)-dien-6-one 532.2 116

5-[3-(6-{[1-(2-Hydroxyethyl)- 1H-pyrazol-4-yl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2- (hydroxymethyl)phenyl]-8-thia-5- azatricyclo[7.40.02,7]trideca- 1(9),2(7)-dien-6-one 547.2 0.006117

2-(2-methyl-3-(5-(5-methyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo- 1,6-dihydropyridazin-3-yl)phenyl)-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1-one 521.2 118

2-(2-(hydroxymethyl)-3-(1- methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4- b]indolizin-1(2H)-one 497.2 119

5-[2-(hydroxymethyl)-3-(5- {[5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3- yl]amino}-1-methyl-6-oxo- 1,6-dihydropyridazin-3-yl)phenyl]-8-thia-5- azatricyclo[7.4.0.0 2,7]trideca-1(9),2(7)-dien-6-one 575.2 0.007 120

5-[5-fluoro-2- (hydroxymethyl)-3-[4- methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinolin-6- ylamino)-4,5-dihydropyrazin-2-yl]phenyl]-8-thia-5- azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-6-one 586 121

5-[2-(hydroxymethyl)-3-(4- methyl-5-oxo-6-{[4- (piperidin-4-yl)phenyl]amino}-4,5- dihydropyrazin-2-yl)phenyl]- 8-thia-5-azatricyclo[7.4.0.02,7]trideca- 1(9),2(7)-dien-6-one 596.3 122

5-[5-fluoro-2- (hydroxymethyl)-3-(4- methyl-6-{[4-(morpholin-4-yl)phenyl]amino}-5-oxo-4,5- dihydropyrazin-2-yl)phenyl]- 8-thia-5-azatricyclo[7.4.0.02,7]trideca- 1(9),2(7)-dien-6-one 616 123

5-(3-{5-[(5-cyclopropyl-1H- pyrazol-3-yl)amino]-1- methyl-6-oxo-1,6-dihydropyridin-3-yl}-2- (hydroxymethyl)phenyl)-8- thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 542.1 0.003 124

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-[(5- methyl-1H-pyrazol-3-yl)amino]-1,2- dihydropyridin-2-one 517 125

3-[(5-ethyl-1H-pyrazol-3- yl)amino]-5-[2- (hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H- pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one 513.3 126

2-(2-(Hydroxymethyl)-3-(1- methyl-6-oxo-5-(4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-ylamino)-1,6-dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 540.3 127

2-(5-fluoro-2- (hydroxymethyl)-3-(4- methyl-6-(4-morpholinophenylamino)-5- oxo-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 599 128

2-(3-(5-(5-(3- hydroxyazetidin-1-yl)pyridin- 2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2- (hydroxymethyl)phenyl)- 3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-1(2H)-one 567.2 129

2-(5-fluoro-2- (hydroxymethyl)-3-(4- methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinolin-6- ylamino)-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 569130

2-(2-(hydroxymethyl)-3-(1- methyl-5-(5-(1- methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6- dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-(2H)-one 593.4 131

5-(3-(6,6-Dimethyl-3,4,6,7- tetrahydro-5H- cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-2- (hydroxymethyl)phenyl)-1- methyl-3-(1-ethyl-1H-pyrazol-4-ylamino)pyrazin- 2(1H)-one 545.1 0.002

TABLE 2 Btk MH+ IC₅₀ No. Structure Name m/z (μMol) 132

2-(2-(hydroxymethyl)-3-(5- (5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3- ylamino)-1-methyl-6-oxo-1,6- dihydropyridazin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 558.3133

5-[2-(hydroxymethyl)-3-[6- oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridazin-3- yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 501.1 134

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-3-{[5-(2- hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3- yl]amino}-1-methyl-1,2- dihydropyridin-2-one 557.3135

3-({5-cyclopropyl- 4H,5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl}amino)-5-[5-fluoro-2-(hydroxymethyl)-3- {1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one598 136

5-(3-{5-[(5-cyclopropyl-1H- pyrazol-3-yl)amino]-1- methyl-6-oxo-1,6-dihydropyridin-3-yl}-5- fluoro-2- (hydroxymethyl)phenyl)-8- thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 560 137

5-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(oxetan-3-yl)-4H,5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3- yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 631 138

3-{[5-(4-ethylpiperazin-1- yl)pyridine-2-yl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one608.3 139

3-{[4-(3-hydroxy-3- methylazetidin-1- yl)phenyl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyrazin-2-one581 140

3-{[1-(2-hydroxyethyl)-1H- pyrazol-4-yl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyrazin-2-one529.59 141

2-(2-(hydroxymethyl)-3-(1- methyl-5-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 570.71 142

3-[(1,5-dimethyl-1H-pyrazol- 3-yl)amino]-5-[2- (hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H- pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one 512.6 143

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[5-(oxetan-3-yl)-4H,5H,6H,7H- pyrazolo[1,5-a]pyrazin-2- yl]amino}-1,2-dihydropyridin-2-one 613.68 144

5-{3-[5-({5-cyclopropyl- 4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-1- methyl-6-oxo-1,6-dihydropyridin-3-yl]-5-fluoro- 2-(hydroxymethyl)phenyl}-8- thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 614.73 145

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[4- (piperidin-4-yl)phenyl]amino}-1,2- dihydropyrazin-2-one 579.4 146

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({5- methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl}amino)-1,2- dihydropyridin-2-one 554 147

6-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-2-methyl-4- {4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-2,3- dihydropyridazin-3-one 542 148

3-[(5-fluoropyridin-2- yl)amino]-5-[2- (hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H- pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one 514 149

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3- {4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,2- dihydropyridin-2-one 559 0.005 150

5-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2- ylamino}-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 576 151

3-{[5-(azetidin-3-yl)pyridine- 2-yl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl]phenyl]-1-methyl-1,2- dihydropyridin-2-one551.3 152

11-[2-(hydroxymethyl)-3-[1- methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl]phenyl]-1,8,11-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),8-dien-10-one 498.2 153

5-[2-(hydroxymethyl)-3-[4- methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinolin-6- ylamino)-4,5-dihydropyrazin-2-yl]phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 568.1 154

5-[2-(hydroxymethyl)-3-[6- oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3- yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 500.1 155

11,11,12,12,13,13- hexahydrogenio-5-[2- (hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylazetidin-3- yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3- yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 588.2 156

3-({5-[(3,3-difluoroazetidin- 1-yl)methyl]-1-methyl-1H-pyrazol-3-yl}amino)-5-[2- (hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H- pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one 604.4 157

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-3-[(5-methoxy-1H-pyrazol-3-yl)amino]-1- methyl-1,2-dihydropyridin-2- one 515.4 158

5-[2-(hydroxymethyl)-3-[1- methyl-6-oxo-5-(5,6,7,8-tetrahydro-1,6-naphthyridin-2- ylamino)-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 568.3 159

5-[2-(hydroxymethyl)-3-[1- methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl]phenyl]-1,5,8-triazatricyclo[7.4.0.0^(2,7)]trideca- 2(7),8-dien-6-one 498.2 160

3-({4-[(2R)-1,4-dimethyl-3- oxopiperazin-2- yl]phenyl}amino)-5-[2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl]phenyl]-1-methyl-1,2- dihydropyrazin-2-one622.4 161

3-{[1-(2-hydroxyethyl)-5- methyl-1H-pyrazol-3- yl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl]phenyl]-1-methyl-1,2- dihydropyridin-2-one543 162

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-[(2-methylpyrimidin-4-yl)amino]- 1,2-dihydropyridin-2-one 511 163

3-{[1-(2-hydroxyethyl)-1H- pyrazol-3-yl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one529 164

5-[3-(5-{[5-(azetidin-3-yl)- 1H-pyrazol-3-yl]amino}-1- methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro- 2-(hydroxymethyl)phenyl]-8- thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 575 165

3-{[5-(azetidin-3-yl)-1H- pyrazol-3-yl]amino}-5-[5-fluoro-2-(hydroxymethyl)-3- {1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one558 166

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3- (5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1,2- dihydropyridin-2-one 551.3 ReplacementSheet 167

10-[2-(hydroxymethyl)-3-[1- methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl]phenyl]-4,4-dimethyl- 1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 511.8 168

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[5-(1-methylazetidin-3-yl)-1H- pyrazol-3-yl]amino}-1,2- dihydropyridin-2-one554 169

5-[2-(hydroxymethyl)-3-(1- methyl-6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2- ylamino}-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 558 170

5-[2-(hydroxymethyl)-3-(1- methyl-5-{[5-(morpholin-4-ylcarbonyl)pyridine-2- yl]amino}-6-oxo-1,6- dihydropyridin-3-yl)phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 626171

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[5- (morpholin-4-ylcarbonyl)pyridine-2- yl]amino}-1,2- dihydropyridin-2-one 609 172

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[5-(1-methylazetidin-3-yl)pyridine- 2-yl]amino}-1,2- dihydropyridin-2-one 565173

10-[2-(hydroxymethyl)-3-(1- methyl-5-{[5-(4- methylpiperazin-1-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 608.4 174

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3- (1,2,3,4-tetrahydroisoquinolin-6- ylamino)-1,2-dihydropyrazin- 2-one 551.4 175

10-[2-(hydroxymethyl)-3-(1- methyl-6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2- ylamino}-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl- 1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 555.3 176

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-3-{[5- (methoxymethyl)-1-methyl-1H-pyrazol-3-yl]amino}-1- methyl-1,2-dihydropyridin-2- one 543Replacement Sheet 177

5-[2-(hydroxymethyl)-3-(5- {[5-(methoxymethyl)-1- methyl-1H-pyrazol-3-yl]amino}-1-methyl-6-oxo- 1,6-dihydropyridin-3- yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 560 178

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-3-{[5- (methoxymethyl)-1-methyl-1H-pyrazol-3-yl]amino}-1- methyl-1,2-dihydropyridin-2- one 561 179

5-[2-(hydroxymethyl)-3-(1- methyl-5-{[5-(1-methylazetidin-3-yl)pyridine- 2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 582 180

6-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-2-methyl-4-[(5- {[methyl(propan-2-yl)amino]methyl}pyridine-2- yl)amino]-2,3- dihydropyridazin-3-one 582.5181

5-[3-(5-{[5-(4-ethylpiperazin- 1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-2- (hydroxymethyl)phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 625.4182

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl]phenyl]-4,4-dimethyl-7- thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 546.2 183

10-[2-(hydroxymethyl)-3-(1- methyl-6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2- ylamino}-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7- thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 572.3 184

10-[2-(hydroxymethyl)-3-[1- methyl-6-oxo-5-(pyridine-2-ylamino)-1,6-dihydropyridin- 3-yl]phenyl]-4,4-dimethyl-7- thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 527.2 185

10-(3-{5-[(1,5-dimethyl-1H- pyrazol-3-yl)amino]-1- methyl-6-oxo-1,6-dihydropyridin-3-yl}-2- (hydroxymethyl)phenyl)-4,4- dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 544.2 186

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-[(5- {[methyl(propan-2-yl)amino]methyl}pyridine-2- yl)amino]-1,2-dihydropyridin- 2-one 581.4187

6-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-4-{[5- (methoxymethyl)-1-methyl-1H-pyrazol-3-yl]amino}-2- methyl-2,3-dihydropyridazin- 3-one 544 188

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({5-[4-(oxetan-3-yl)piperazin-1- yl]pyridine-2-yl}amino)-1,2-dihydropyridin-2-one 636 189

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl]phenyl]-4,4-dimethyl- 1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 529.7 190

10-[3-(5-{[5-(4- ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo- 1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl]-4,4- dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 622.5 191

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2- ylamino}-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl- 1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 573.4 192

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2- ylamino}-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7- thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 590.2 193

10-[2-(hydroxymethyl)-3-[4- methyl-5-oxo-6-(pyridine-3-ylamino)-4,5-dihydropyrazin- 2-yl]phenyl]-4,4-dimethyl-7- thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 528.2 194

10-[2-(hydroxymethyl)-3-(1- methyl-5-{[5-(4- methylpiperazin-1-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7- thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 625.3 195

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({5-[4-(propan-2-yl)piperazin-1- yl]pyridine-2-yl}amino)-1,2-dihydropyridin-2-one 622 196

10-(3-{5-[(1,5-dimethyl-1H- pyrazol-3-yl)amino]-1- methyl-6-oxo-1,6-dihydropyridin-3-yl}-5- fluoro-2- (hydroxymethyl)phenyl)-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one545.4 197

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methylpiperazin-1-yl)pyridine-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 612.50.002 198

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(4-methylpiperazin-1-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 626 199

5-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[(1-methylazetidin-3-yl)oxy]pyridine-2-yl}amino)- 6-oxo-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 616 200

3-{[5-(azetidin-1-ylmethyl)-1- methyl-1H-pyrazol-3-yl]amino}-5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H- pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one 586.5 201

3-{[5-(4-ethylpiperazin-1- yl)pyridine-2-yl]amino}-5-[5-fluoro-2-(hydroxymethyl)-3- {1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one626.4 202

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[5-(1-methylpyrrolidin-2- yl)pyridine-2-yl]amino}-1,2- dihydropyridin-2-one597.4 203

10-[2-(hydroxymethyl)-3-[1- methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl]phenyl]-4,4-dimethyl-7- thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6),11-trien-9-one 526.2 204

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(4-methylpiperazin-1-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7- thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 643.3 205

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-[(6-methyl-5,6,7,8-tetrahydro-1,6- naphthyridin-2-yl)amino]-1,2-dihydropyridin-2-one 583 206

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({1-[2-(methylamino)ethyl]-1H- pyrazol-3-yl}amino)-1,2- dihydropyridin-2-one542 207

3-{[5-(3-hydroxy-3- methylazetidin-1-yl)pyridine- 2-yl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one581 208

3-[(6-ethyl-5,6,7,8-tetrahydro- 1,6-naphthyridin-2-yl)amino]-5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one597 209

5-[2-(hydroxymethyl)-3-[1- methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 653 210

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridine-2- ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 654 0.0039 211

5-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 671 212

2-(5-Fluoro-2- hydroxymethyl-3-{1-methyl- 5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo- 1,6-dihydro-pyridin-3-yl}-phenyl)-3,4,5,6,7,8- hexahydro-2H- benzo[4,5]thieno[2,3-c]pyridine-1-one 629 0.0010 213

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[5-(1-methylazetidin-3-yl)pyridine- 2-yl]amino)-1,2- dihydropyridin-2-one 583214

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({4-[1-(oxetan-3-yl)piperidin-4- yl]phenyl}amino)-1,2- dihydropyrazin-2-one653.6 215

10-[5-fluoro-2- (hydroxymethyl)-3-(4-methyl- 6-{[4-(1-methylazetidin-3-yl)phenyl]amino}-5-oxo-4,5- dihydropyrazin-2-yl)phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one597.5 216

[(2-{4,4-dimethyl-9-oxo-7- thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-6-[1- methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl]phenyl)methoxy] phosphonic acid 608.2217

10-{5-fluoro-3-[5-({5-[4-(2- fluoroethyl)piperazin-1-yl]pyridine-2-yl}amino)-1- methyl-6-oxo-1,6- dihydropyridin-3-yl]-2-(hydroxymethyl)phenyl}-4,4- dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 675.3 218

5-(3-{5-[(6-ethyl-5,6,7,8- tetrahydro-1,6-naphthyridin-2-yl)amino]-1-methyl-6-oxo- 1,6-dihydropyridin-3-yl}-5- fluoro-2-(hydroxymethyl)phenyl)-8- thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 614 219

5-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2- yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 642 220

5-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]pyridine-2- yl}amino)-1,6-dihydropyridin-3-yl]phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 657 221

5-[5-Fluoro-2- (hydroxymethyl)-3-{4- methyl-6-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6- yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 600 222

5-[5-fluoro-2- (hydroxymethyl)-3-(4-methyl- 6-{[2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6- yl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 642 223

5-[5-fluoro-2- (hydroxymethyl)-3-{1- methyl-5-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2- yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 600 224

10-[5-fluoro-2- (hydroxymethyl)-3-{1- methyl-5-[(5- {[methyl(propan-2-yl)amino]methyl}pyridine-2- yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 613.6 225

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2- yl}phenyl]-1-methyl-3-[(5-methyl-1H-pyrazol-3- yl)amino]-1,2-dihydropyridin- 2-one 499.2 226

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2- yl}phenyl]-1-methyl-3-(5,6,7,8-tetrahydro-2,6- naphthyridin-3-ylamino)-1,2-dihydropyridin-2-one 551.2 227

3-{[5-(azetidin-3-yl)pyridine- 2-yl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one551.2 228

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2- yl}phenyl]-1-methyl-3- (1,2,3,4-tetrahydroisoquinolin-6- ylamino)-1,2-dihydropyrazin- 2-one 551.2 229

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2- yl}phenyl]-1-methyl-3-{[5-(1-methylpyrrolidin-2- yl)pyridine-2-yl]amino}-1,2- dihydropyridin-2-one579.2 230

10-[3-(5-{[5-(azetidin-1- ylmethyl)-1-methyl-1H- pyrazol-3-yl]amino}-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 600.6 231

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-[(2-methyl-2,3-dihydro-1H- isoindol-5-yl)amino]-1,2- dihydropyrazin-2-one569 232

5-[5-fluoro-2- (hydroxymethyl)-3-{4- methyl-6-[(2-methyl-2,3-dihydro-1H-isoindol-5- yl)amino]-5-oxo-4,5- dihydropyrazin-2-yl}phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 586233

5-[3-(5-{[5-(1-ethylazetidin- 3-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-8- thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 614 234

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({5- methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl)amino)-1,2- dihydropyridin-2-one 572 235

10-[5-fluoro-2- (hydroxymethyl)-3-{4- methyl-6-[(2-methyl-2,3-dihydro-1H-isoindol-5- yl)amino]-5-oxo-4,5- dihydropyrazin-2-yl}phenyl]-4,4-dimethyl-7-thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 600.2 236

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(3-methylazetidin-1-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7- thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 614.3 237

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2- yl)amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 685.4 238

10-[3-(5-{[5-(4- ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo- 1,6-dihydropyridin-3-yl)-5- fluoro-2-(hydroxymethyl)phenyl]-4,4- dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 640.6 239

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]pyridine-2- yl}amino)-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 671.3 240

10-[5-fluoro-2- (hydroxymethyl)-3-{1- methyl-5-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2- yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]- 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 614.3 241

10-(3-{5-[(6-ethyl-5,6,7,8- tetrahydro-1,6-naphthyridin-2-yl)amino]-1-methyl-6-oxo- 1,6-dihydropyridin-3-yl}-5- fluoro-2-(hydroxymethyl)phenyl)-4,4- dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 628.3 242

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[5-(1-methylpiperidin-4-yl)pyridine- 2-yl]amino)-1,2- dihydropyridin-2-one611.5 243

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylpyrrolidin-2- yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3- yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 611.5 244

10-[5-fluoro-2- (hydroxymethyl)-3-[4-methyl- 6-({4-[1-(oxetan-3-yl)piperidin-4- yl]phenyl}amino)-5-oxo-4,5- dihydropyrazin-2-yl]phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one667.6 245

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]pyridine-2- yl}amino)-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 654.6 246

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 586.6 247

10-[5-fluoro-2- (hydroxymethyl)-3-{4- methyl-6-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6- yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]- 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 614 248

10-(3-{6-[(2-ethyl-1,2,3,4- tetrahydroisoquinolin-6-yl)amino]-4-methyl-5-oxo- 4,5-dihydropyrazin-2-yl}-5- fluoro-2-(hydroxymethyl)phenyl)-4,4- dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 628 249

10-[5-fluoro-2- (hydroxymethyl)-3-(4-methyl-6-{[2-(oxetan-3-yl)-1,2,3,4- tetrahydroisoquinolin-6-yl]amino}-5-oxo-4,5- dihydropyrazin-2-yl)phenyl]-4,4-dimethyl-7-thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 656 250

3-{[5-(1-ethylazetidin-3- yl)pyridine-2-yl]amino}-5-[5-fluoro-2-(hydroxymethyl)-3- {1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one597 251

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[(1-methylazetidin-3-yl)oxy]pyridine-2-yl}amino)- 6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-7- thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 630.3 252

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(oxetan-3-yl)-4H,5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3- yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 628.5 253

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({5-[(2R)-1-methylpyrrolidin-2- yl]pyridine-2-yl}amino)-1,2-dihydropyridin-2-one 597.4 254

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({5-[(2S)-1-methylpyrrolidin-2- yl]pyridine-2-yl}amino)-1,2-dihydropyridin-2-one 597.4 255

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[5-(morpholin-4-yl)pyridine-2- yl]amino}-1,2- dihydropyridin-2-one 599 256

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(morpholin-4-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7- thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 630 257

10-[3-(5-{[5-(1-ethylazetidin- 3-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]- 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 628 258

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[2-(oxetan-3-yl)-1,2,3,4- tetrahydroisoquinolin-6- yl]amino}-1,2-dihydropyridin-2-one 624 259

5-[2-(hydroxymethyl)-3-[1- methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3- yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 571 260

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(1-methylpiperidin-4-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 625.5 261

10-[5-fluoro-2- (hydroxymethyl)-3-{1- methyl-5-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2- yl)amino]-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 597.5 262

10-[3-(5-{[5-(1-ethylazetidin- 3-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 611.5 263

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-3-[(2- methoxypyrimidin-4-yl)amino]-1-methyl-1,2- dihydropyridin-2-one 545.5 264

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[1-(oxetan-3-yl)piperidin-4-yl]pyridine-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 667.6 265

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({5-[1-(oxetan-3-yl)piperidin-4- yl]pyridine-2-yl]amino)-1,2-dihydropyridin-2-one 653.6 0.0028 266

10-[5-fluoro-2- (hydroxymethyl)-3-{4- methyl-6-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6- yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 597.4 267

5-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(1-methylpiperidin-4-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 628 0.0038 268

5-{3-[5-({5-[2- (dimethylamino)ethoxy]pyridine- 2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]- 5-fluoro-2- (hydroxymethyl)phenyl}-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 6180.0020 269

5-[3-(5-{[5-(4-ethylpiperazin- 1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-8- thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 643.4 0.004 270

10-(3-{5-[(5-{[2- (dimethylamino)ethyl](methyl)amino}pyridine-2-yl)amino]- 1-methyl-6-oxo-1,6- dihydropyridin-3-yl}-5-fluoro-2- (hydroxymethyl)phenyl)-4,4- dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 645.3 0.0040 271

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(1-methylazetidin-3-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 597.4 0.0047 272

10-[3-(5-{[5-(4- ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo- 1,6-dihydropyridin-3-yl)-5- fluoro-2-(hydroxymethyl)phenyl]-4,4- dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 657.6 0.0064 273

10-{5-fluoro-3-[5-({5-[4-(2- fluoroethyl)piperazin-1-yl]pyridine-2-yl}amino)-1- methyl-6-oxo-1,6- dihydropyridin-3-yl]-2-(hydroxymethyl)phenyl}-4,4- dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 658.5 0.00635 274

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(morpholin-4-ylmethyl)pyridine-2- yl]amino}-6-oxo-1,6- dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one627.5 0.00234 275

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2- yl}phenyl]-1-methyl-3-{[5-(4-methylpiperazin-1- yl)pyridine-2-yl]amino}-1,2- dihydropyridin-2-one594.3 0.0163 276

10-[5-fluoro-2- (hydroxymethyl)-3-{1- methyl-5-[(5-methyl-1H-pyrazol-3-yl)amino]-6-oxo- 1,6-dihydropyridin-3-yl}phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 531.4 0.0022 277

5-[5-fluoro-2- (hydroxymethyl)-3-{1- methyl-5-[(5- {[methyl(propan-2-yl)amino]methyl}pyridine-2- yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 616.4 0.0034 278

10-[5-fluoro-2- (hydroxymethyl)-3-(4-methyl- 6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-oxo-4,5- dihydropyrazin-2-yl)phenyl]-4,4-dimethyl-7-thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 642 0.0026 279

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 603 0.0049 280

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl-5-{[6-(oxetan-3-yl)-5,6,7,8- tetrahydro-1,6-naphthyridin-2-yl]amino}-6-oxo-1,6- dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7-thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 656 0.0042 281

5-[5-fluoro-2- (hydroxymethyl)-3-(4-methyl- 6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-oxo-4,5- dihydropyrazin-2-yl)phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 628 0.0052 282

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[4-(1- methylpiperidin-4-yl)phenyl]amino}-1,2- dihydropyrazin-2-one 611 0.004 283

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-[(2- methyl-1,2,3,4-tetrahydroisoquinolin-6- yl)amino]-1,2-dihydropyrazin- 2-one 583 0.0081284

10-(3-{5-[(6-ethyl-5,6,7,8- tetrahydro-1,6-naphthyridin-2-yl)amino]-1-methyl-6-oxo- 1,6-dihydropyridin-3-yl}-5- fluoro-2-(hydroxymethyl)phenyl)-4,4- dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 611.5 0.0028 285

10-{3-[5-({5-ethyl- 4H,5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl]amino)-1-methyl-6-oxo-1,6- dihydropyridin-3-yl]-5-fluoro-2-(hydroxymethyl)phenyl}- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 600.6 0.0036 286

5-(3-{5-[(5-{[2- (dimethylamino)ethyl](methyl)amino}pyridine-2-yl)amino]- 1-methyl-6-oxo-1,6- dihydropyridin-3-yl}-5-fluoro-2- (hydroxymethyl)phenyl)-8- thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 631.3 0.0034 287

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylpyrrolidin-2- yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3- yl)phenyl]-4,4-dimethyl-7- thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 628.3 0.0014 288

5-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(1-methylpyrrolidin-2-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 614.3 0.0021 289

5-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(morpholin-4-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 616.3 0.0050 290

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[(2S)-1-methylpyrrolidin-2- yl]pyridine-2-yl}amino)-6- oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 611.5 291

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[(2R)-1-methylpyrrolidin-2- yl]pyridine-2-yl}amino)-6- oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 611.5 0.00174 292

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl-5-{[6-(oxetan-3-yl)-5,6,7,8- tetrahydro-1,6-naphthyridin-2-yl]amino}-6-oxo-1,6- dihydropyridin-3-yl)phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 639.5 0.0116 293

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({5- [(1-methylazetidin-3-yl)oxy]pyridine-2-yl}amino)- 1,2-dihydropyridin-2-one 599 0.0098 294

10-[5-fluoro-2- (hydroxymethyl)-3-(4-methyl- 6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-oxo-4,5- dihydropyrazin-2-yl)phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one625 0.016 295

10-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(1-methylpiperidin-4-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7- thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 642 0.0022 296

10-{3-[5-({5-[2- (dimethylamino)ethoxy]pyridine- 2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]- 5-fluoro-2- (hydroxymethyl)phenyl}-4,4-dimethyl-7-thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 632 0.0030 297

3-({5-[2- (dimethylamino)ethoxy]pyridine- 2-yl}amino)-5-[5-fluoro-2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one601 0.0042 298

10-[5-fluoro-2- (hydroxymethyl)-3-(4-methyl- 6-{[4-(1-methylazetidin-3-yl)phenyl]amino}-5-oxo-4,5- dihydropyrazin-2-yl)phenyl]-4,4-dimethyl-7-thia-10- azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 614 0.0053 299

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[1-(oxetan-3-yl)piperidin-4-yl]pyridine-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 684.5 0.0087 300

10-[5-fluoro-2- (hydroxymethyl)-3-{5-[(2- methoxypyrimidin-4-yl)amino]-1-methyl-6-oxo- 1,6-dihydropyridin-3-yl}phenyl]-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 559.4 0.0034 301

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[5-(piperazin-1-yl)pyridine-2- yl]amino}-1,2- dihydropyridin-2-one 580.40.0061 302

10-(3-{5-[(1-ethyl-5-methyl- 1H-pyrazol-3-yl)amino]-1- methyl-6-oxo-1,6-dihydropyridin-3-yl}-5- fluoro-2- (hydroxymethyl)phenyl)-4,4-dimethyl-1,10- diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one559.4 0.0099 303

5-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[1-(oxetan-3-yl)piperidin-4-yl]pyridine-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 670.3 0.0049 304

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 668 0.0078 305

5-[2-(hydroxymethyl)-3-[4- methyl-6-({4-[1-(oxetan-3- yl)piperidin-4-yl]phenyl}amino)-5-oxo-4,5- dihydropyrazin-2-yl]phenyl]- 8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 652 0.0171 306

10-[2-(hydroxymethyl)-3-[1- methyl-6-oxo-5-(pyrimidin-4- ylamino)-1,6-dihydropyridazin-3- yl]phenyl]-4,4-dimethyl-7- thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 529.3 307

6-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-2-methyl-4-{[5-(4- methylpiperazin-1-yl)pyridine-2-yl]amino}-2,3- dihydropyridazin-3-one 595.6 0.0071 308

5-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(1-methylpyrrolidin-3-yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 614.3 0.0033 309

5-[2-(hydroxymethyl)-3-{1- oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2- yl}phenyl]-1-methyl-3- {4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,2- dihydropyridin-2-one 541.2 0.0165 310

3-{[5-(4-ethylpiperazin-1- yl)pyridine-2-yl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2- yl}phenyl]-1-methyl-1,2- dihydropyridin-2-one608.3 0.0166 311

10-[2-(hydroxymethyl)-3-[1- methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 650 0.0052 312

10-[2-(hydroxymethyl)-3-[1- methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 667 0.043Replacement Sheet 313

5-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(2S)-(1-methylpyrrolidin-2- yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 614.2 314

5-[5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-{[5-(2R)-(1-methylpyrrolidin-2- yl)pyridine-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5- azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one 614.2 315

5-[2-(hydroxymethyl)-5-[1- methyl-5-({4-[1-methylpiperidin-4-yl]pyridine- 2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)- dien-6-one 610 316

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-[(4-(1- methylazetidin-3-yl)phenyl)amino)-1,2- dihydropyrazin-2-one 583 317

10-[2-(hydroxymethyl)-3-[1- methyl-5-({5-(oxetan-3-yl)-4H,5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3- yl]phenyl]-4,4-dimethyl-7- thia-10-azatricyclo-[6.4.0.0^(2,6)]dodeca-1(8),2(6)- dien-9-one 627 318

10-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-(oxetan-3-yl)-4H,5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3- yl]phenyl]-4,4-dimethyl-7- thia-10-azatricyclo-[6.4.0.0^(2,6)]dodeca-1(8),2(6)- dien-9-one 645.3 319

2-(2-(Hydroxymethyl)-3-(1- methyl-5-(5-(oxetan-3-yl)- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 596 Replacement Sheet 320

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2- yl}phenyl]-3-{1-methyl-5-(N-methyl,N-oxetan-3- ylaminomethyl-1H-pyrazol-3- yl)amino}-1,2-dihydropyridin-2-one 616 321

10-[5-Fluoro-2- (Hydroxymethyl)-3-{1- methyl-5-[(1-methyl-5-{[methyl(oxetan-3- yl)amino]methyl}-1H- pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3- yl}phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca- 2(6),7-dien-9-one 630 322

10-[5-Fluoro-2- (hydroxymethyl)-3-{1- methyl-5-[(1-methyl-5-{[methyl(oxetan-3- yl)amino]methyl}-1H- pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3- yl}phenyl]-4,4-dimethyl-7- thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca- 1(8),2(6)-dien-9-one 647 323

10-[2-(Hydroxymethyl)-3-(1- methyl-5-{[5-(1-methylpiperidin-4-yl)pyridin- 2-yl]amino}-6-oxopyridin-3-yl)phenyl]-4,4-dimethyl-1,10- diaza- tricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one 607 324

5-[5-fluoro-2- (hydroxymethyl)-5-[1-methyl- 5-({l-methyl-5-(N-methyl, N-oxetan-3-ylaminomethyl)-1H- pyrazol-3-yl}amino)-6-oxo-1,6-dihydropyridin-3- yl]phenyl]-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca- 1(9),2(7)-dien-6-one 633 325

10-[2-(hydroxymethyl)-3-[1- methyl-5-({5-[1- (methylpiperidin-4-yl)pyridine-2-yl)amino)-6- oxo-1,6-dihydropyridin-3-yl)phenyl)-4,4-dimethyl-7- thia-10-azatricyclo-[6.4.0.0^(2,6)]dodeca-1(8),2(6)- dien-9-one 624 326

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methylpiperazin-1-yl)pyridine-2-ylamino)-6-oxo- 1,6-dihydropyridin-3- yl)phenyl)-3,4-dihydropyrazino[1,2-a]indol- 1(2H)-one 608 327

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[4-(oxetan-3-yl)piperazin-1- yl]}phenyl}amino}-1,2- dihydropyrazin-2-one654.8 328

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-2-methyl-4-{[4-(oxetan-3-yl)piperazin-1- yl]}phenyl}amino}-2,3- dihydropyrazin-3-one655.3 329

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methylpiperazin-1-yl)pyridine-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-3,4-dihydro-2H- [1]benzothiolo[2,3-c]pyridine- 1-one 625 330

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-({5-[4-(oxetan-3-yl)piperazin-1- yl]pyrazin-2-yl}amino)-1,2-dihydropyridin-2-one 655 331

5-[5-fluoro-2- (hydroxymethyl)-3-{1-oxo- 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2- yl}phenyl]-1-methyl-3-{[4- methylpiperazin-1-yl]phenyl]amino}-1,2- dihydropyrazin-2-one 613 332

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methyl-2-oxopiperazin-1-yl)pyridine-2- ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 626 333

2-(5-fluoro-2- (methoxymethyl)-3-(1- methyl-5-(5-(4- methylpiperazin-1-yl)pyridine-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 626 334

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-(oxetan-3-yl)-piperazin-1-yl)pyridine-2- ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9-hexahydro-6,9-methanopyrazino[1,2-a]indol- 1(2H)-one 666 Replacement Sheet 335

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-6-oxo-1,6- dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-1(2H)-one 638.3 336

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methyl-3-fluoromethyl-piperazin-1- yl)pyridine-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 644 337

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin- 3-yl)phenyl)-3,4,6,7,8,9- hexahydro-6,9-methanopyrazino[1,2-a]indol- 1(2H)-one 527 338

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methyl-1,4-diazepan-1-ylpyridin-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 626 339

5-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2- yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]- 8-thia-4,5- diazatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7),3(4)-trien-6- one 670 340

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methylpiperazin-1-ylpyridin-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydro-6,9- methanopyrazino[1,2-a]indol-1(2H)-one 624 341

5-[5-fluoro-2- (hydroxymethyl)-3-[1-methyl- 5-({5-[4-methylpiperazin-1-yl]pyridine-2-yl}amino)-6- oxo-1,6-dihydropyridin-3-yl]phenyl]-8-thia-4,5- diazatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7),3(4)-trien-6- one 628 342

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(6-(4-methylpiperazin-1-yl)pyridazin-3-ylamino)-6- oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 613

TABLE 3 MH+ No. Structure Name m/z 343

2-(5-fluoro-2- (methoxymethyl)-3-(1- methyl-5-(5-(4-methylpiperazin-1-yl)pyridin- 2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 626.3 344

4-fluoro-2-(1-methyl-5-(5-(4- methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6- dihydropyridin-3-yl)-6-(1- oxo-3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-2(1H)-yl)benzyl acetate 654.3 345

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methyl-2-oxopiperazin-1-yl)pyridin-2- ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 626.3 346

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridazin-3- ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 655.3 347

4-(6-(5-(5-fluoro-2- (hydroxymethyl)-3-(1-oxo- 3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-2(1H)-yl)phenyl)-1- methyl-2-oxo-1,2-dihydropyridin-3- ylamino)pyridin-3-yl)-1- methylpiperazine 1-oxide628.3 348

1-(6-(5-(5-fluoro-2- (hydroxymethyl)-3-(1-oxo- 3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-2(1H)-yl)phenyl)-1- methyl-2-oxo-1,2-dihydropyridin-3- ylamino)pyridin-3-yl)-4- methylpiperazine 1,4-dioxide644.3 349

2-(5-fluoro-2- (hydroxymethyl)-3-(4-methyl- 6-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)-5-oxo- 4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 613.3350

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methylmorpholin-2-yl)pyridin-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 613.3351

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7- yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 654.3 352

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methylmorpholin-2-yl)pyridin-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 613.3353

2-(5-fluoro-2- (hydroxymethyl)-3-(4-methyl- 6-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3- ylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 655.3 354

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 6-oxo-5-(3-(4-(oxetan-3-yl)piperazin-1-yl)pyrid-6- ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydro-6,9- methanopyrazino[1,2-a]indol-1(2H)-one 666.3 355

2-(6-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 612.3356

2-(6-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2- ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 654.3 357

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 6-oxo-5-(3-(4-methylpiperazin-1-yl)pyrid-6- ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydro-6,9- methanopyrazino[1,2-a]indol-1(2H)-one 624.3 358

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(6-methyl-2,6-diazaspiro[3.3]heptan-2- yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 624.3 359

3-(5-Fluoro-2- hydroxymethyl-3-{1-methyl- 5-[6-(4-methyl-piperazin-1-yl)-pyridazin-3-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6,7,8,9- tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyridazin-4-one 629.2 360

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 6-oxo-5-(3-(4-methylpiperazin-1- yl)pyridazin-6-ylamino)-1,6-dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9-hexahydro-6,9-methanopyrazino[1,2-a]indol- 1(2H)-one 625.3 361

3-(5-Fluoro-2- hydroxymethyl-3-{1-methyl- 5-[6-(4-oxetan-3-yl-piperazin-1-yl)-pyridazin-3-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6,7,8,9- tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyridazin-4-one 671.2 362

2-(5-Fluoro-2- hydroxymethyl-3-{1-methyl- 5-[6-(4-oxetan-3-yl-piperazin-1-yl)-pyridazin-3-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4,5,6,7,8- hexahydro-2H- benzo[4,5]thieno[2,3-c]pyridin-1-one 672.3 363

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 6-oxo-5-(3-(4-(oxetan-3-yl)piperazin-1-yl)pyridazin-6- ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydro-6,9- methanopyrazino[1,2-a]indol-1(2H)-one 667.3 364

2-(5-fluoro-2- (hydroxymethyl)-3-(5-(5-(4- methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6- dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9-hexahydropyrazino[1,2- a]indol-1(2H)-one 598.3 365

4-fluoro-2-(1-methyl-5-(5-(4- (oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-2(1H)-yl)benzyl acetate696.3 366

2-(5-fluoro-2- (hydroxymethyl)-3-(5-(5-(4- (oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 640.3367

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2- ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)- 6,7,8,9-tetrahydro-[1,2,4]triazino[4,5-a]indol- 1(2H)-one 653.3 368

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-6,7,8,9-tetrahydro- [1,2,4]triazino[4,5-a]indol- 1(2H)-one611.3 369

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(5-(4-(oxetan-3-yl)-1,4-diazepan-1-yl)pyridin-2- ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)- 3,4,6,7,8,9- hexahydropyrazino[1,2-a]indol-1(2H)-one 668.3 370

2-(5-fluoro-2- (hydroxymethyl)-3-(1-methyl- 5-(4-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo- 1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9- hexahydropyrazino[1,2- a]indol-1(2H)-one 612.3371

2-(5-Fluoro-2- hydroxymethyl-3-{1-methyl- 5-[5-(4-oxetan-3-yl-[1,4]diazepan-1-yl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4,5,6,7,8-hexahydro-2H- benzo[4,5]thieno[2,3-c]pyridin-1-one 685.3Administration of Formula I Compounds

The compounds of the invention may be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, parenteral (including subcutaneous, intramuscular, intravenous,intraarterial, intradermal, intrathecal and epidural), transdermal,rectal, nasal, topical (including buccal and sublingual), vaginal,intraperitoneal, intrapulmonary and intranasal. For localimmunosuppressive treatment, the compounds may be administered byintralesional administration, including perfusing or otherwisecontacting the graft with the inhibitor before transplantation. It willbe appreciated that the preferred route may vary with for example thecondition of the recipient. Where the compound is administered orally,it may be formulated as a pill, capsule, tablet, etc. with apharmaceutically acceptable carrier or excipient. Where the compound isadministered parenterally, it may be formulated with a pharmaceuticallyacceptable parenteral vehicle and in a unit dosage injectable form, asdetailed below.

A dose to treat human patients may range from about 10 mg to about 1000mg of Formula I compound. A typical dose may be about 100 mg to about300 mg of the compound. A dose may be administered once a day (QID),twice per day (BID), or more frequently, depending on thepharmacokinetic and pharmacodynamic properties, including absorption,distribution, metabolism, and excretion of the particular compound. Inaddition, toxicity factors may influence the dosage and administrationregimen. When administered orally, the pill, capsule, or tablet may beingested daily or less frequently for a specified period of time. Theregimen may be repeated for a number of cycles of therapy.

Methods of Treatment with Formula I Compounds

Formula I compounds of the present invention are useful for treating ahuman or animal patient suffering from a disease or disorder arisingfrom abnormal cell growth, function or behavior associated with Btkkinase such as an immune disorder, cardiovascular disease, viralinfection, inflammation, a metabolism/endocrine disorder or aneurological disorder, may thus be treated by a method comprising theadministration thereto of a compound of the present invention as definedabove. A human or animal patient suffering from cancer may also betreated by a method comprising the administration thereto of a compoundof the present invention as defined above. The condition of the patientmay thereby be improved or ameliorated.

Formula I compounds may be useful for in vitro, in situ, and in vivodiagnosis or treatment of mammalian cells, organisms, or associatedpathological conditions, such as systemic and local inflammation,immune-inflammatory diseases such as rheumatoid arthritis, immunesuppression, organ transplant rejection, allergies, ulcerative colitis,Crohn's disease, dermatitis, asthma, systemic lupus erythematosus,Sjögren's Syndrome, multiple sclerosis, scleroderma/systemic sclerosis,idiopathic thrombocytopenic purpura (ITP), anti-neutrophil cytoplasmicantibodies (ANCA) vasculitis, chronic obstructive pulmonary disease(COPD), psoriasis, and for general joint protective effects.

Methods of the invention also include treating such diseases asarthritic diseases, such as rheumatoid arthritis, monoarticulararthritis, osteoarthritis, gouty arthritis, spondylitis; Behcet disease;sepsis, septic shock, endotoxic shock, gram negative sepsis, grampositive sepsis, and toxic shock syndrome; multiple organ injurysyndrome secondary to septicemia, trauma, or hemorrhage; ophthalmicdisorders such as allergic conjunctivitis, vernal conjunctivitis,uveitis, and thyroid-associated ophthalmopathy; eosinophilic granuloma;pulmonary or respiratory disorders such as asthma, chronic bronchitis,allergic rhinitis, ARDS, chronic pulmonary inflammatory disease (e.g.,chronic obstructive pulmonary disease), silicosis, pulmonarysarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia,bronchiectasis, and pulmonary oxygen toxicity; reperfusion injury of themyocardium, brain, or extremities; fibrosis such as cystic fibrosis;keloid formation or scar tissue formation; atherosclerosis; autoimmunediseases, such as systemic lupus erythematosus (SLE), autoimmunethyroiditis, multiple sclerosis, some forms of diabetes, and Reynaud'ssyndrome; and transplant rejection disorders such as GVHD and allograftrejection; chronic glomerulonephritis; inflammatory bowel diseases suchas chronic inflammatory bowel disease (CIBD), Crohn's disease,ulcerative colitis, and necrotizing enterocolitis; inflammatorydermatoses such as contact dermatitis, atopic dermatitis, psoriasis, orurticaria; fever and myalgias due to infection; central or peripheralnervous system inflammatory disorders such as meningitis, encephalitis,and brain or spinal cord injury due to minor trauma; Sjogren's syndrome;diseases involving leukocyte diapedesis; alcoholic hepatitis; bacterialpneumonia; antigen-antibody complex mediated diseases; hypovolemicshock; Type I diabetes mellitus; acute and delayed hypersensitivity;disease states due to leukocyte dyscrasia and metastasis; thermalinjury; granulocyte transfusion-associated syndromes; andcytokine-induced toxicity.

The methods of the invention can have utility in treating subjects whoare or can be subject to reperfusion injury, i.e., injury resulting fromsituations in which a tissue or organ experiences a period of ischemiafollowed by reperfusion. The term “ischemia” refers to localized tissueanemia due to obstruction of the inflow of arterial blood. Transientischemia followed by reperfusion characteristically results inneutrophil activation and transmigration through the endothelium of theblood vessels in the affected area. Accumulation of activatedneutrophils in turn results in generation of reactive oxygenmetabolites, which damage components of the involved tissue or organ.This phenomenon of “reperfusion injury” is commonly associated withconditions such as vascular stroke (including global and focalischemia), hemorrhagic shock, myocardial ischemia or infarction, organtransplantation, and cerebral vasospasm. To illustrate, reperfusioninjury occurs at the termination of cardiac bypass procedures or duringcardiac arrest when the heart, once prevented from receiving blood,begins to reperfuse. It is expected that inhibition of Btk activity mayresult in reduced amounts of reperfusion injury in such situations.

Pharmaceutical Formulations

In order to use a compound of this invention for the therapeutictreatment of mammals including humans, it is normally formulated inaccordance with standard pharmaceutical practice as a pharmaceuticalcomposition. According to this aspect of the invention there is provideda pharmaceutical composition comprising a compound of this invention inassociation with a pharmaceutically acceptable diluent or carrier.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent) is dissolved in a suitable solvent in the presence of one or moreof the excipients described above. The compound of the present inventionis typically formulated into pharmaceutical dosage forms to provide aneasily controllable dosage of the drug and to enable patient compliancewith the prescribed regimen.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Pharmaceutical formulations of the compounds of the present inventionmay be prepared for various routes and types of administration. Forexample, a compound of Formula I having the desired degree of purity mayoptionally be mixed with pharmaceutically acceptable diluents, carriers,excipients or stabilizers (Remington's Pharmaceutical Sciences (1980)16th edition, Osol, A. Ed.), in the form of a lyophilized formulation,milled powder, or an aqueous solution. Formulation may be conducted bymixing at ambient temperature at the appropriate pH, and at the desireddegree of purity, with physiologically acceptable carriers, i.e.,carriers that are non-toxic to recipients at the dosages andconcentrations employed. The pH of the formulation depends mainly on theparticular use and the concentration of compound, but may range fromabout 3 to about 8. Formulation in an acetate buffer at pH 5 is asuitable embodiment.

The compound ordinarily can be stored as a solid composition, alyophilized formulation or as an aqueous solution.

The pharmaceutical compositions of the invention will be formulated,dosed and administered in a fashion, i.e., amounts, concentrations,schedules, course, vehicles and route of administration, consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. The “therapeutically effective amount”of the compound to be administered will be governed by suchconsiderations, and is the minimum amount necessary to ameliorate, ortreat the hyperproliferative disorder.

As a general proposition, the initial pharmaceutically effective amountof the inhibitor administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient bodyweight per day, with the typical initial range of compound used being0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Theactive pharmaceutical ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations of compounds of Formula I may beprepared. Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

Formulations of a compound of Formula I suitable for oral administrationmay be prepared as discrete units such as pills, capsules, cachets ortablets each containing a predetermined amount of a compound of FormulaI. Compressed tablets may be prepared by compressing in a suitablemachine the active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs may be prepared for oral use. Formulationsof compounds of Formula I intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipient which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,calcium or sodium phosphate; granulating and disintegrating agents, suchas maize starch, or alginic acid; binding agents, such as starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc. Tablets may be uncoated or may be coated by knowntechniques including microencapsulation to delay disintegration andadsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate alone or with a wax may beemployed.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientsmay be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients may be formulated in a creamwith an oil-in-water cream base. If desired, the aqueous phase of thecream base may include a polyhydric alcohol, i.e., an alcohol having twoor more hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations may desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs. The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it desirably comprises a mixture ofat least one emulsifier with a fat or an oil or with both a fat and anoil. Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

Aqueous suspensions of Formula I compounds contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension may also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

The pharmaceutical compositions of compounds of Formula I may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butanediol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

Combination Therapy

The compounds of Formula I may be employed alone or in combination withother therapeutic agents for the treatment of a disease or disorderdescribed herein, such as inflammation or a hyperproliferative disorder(e.g., cancer). In certain embodiments, a compound of Formula I iscombined in a pharmaceutical combination formulation, or dosing regimenas combination therapy, with a second therapeutic compound that hasanti-inflammatory or anti-hyperproliferative properties or that isuseful for treating an inflammation, immune-response disorder, orhyperproliferative disorder (e.g., cancer). The second therapeutic agentmay be an NSAID anti-inflammatory agent. The second therapeutic agentmay be a chemotherapeutic agent. The second compound of thepharmaceutical combination formulation or dosing regimen preferably hascomplementary activities to the compound of Formula I such that they donot adversely affect each other. Such compounds are suitably present incombination in amounts that are effective for the purpose intended. Inone embodiment, a composition of this invention comprises a compound ofFormula I, or a stereoisomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof, in combination witha therapeutic agent such as an NSAID.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein preferably there is a time period while both (orall) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other therapeutic agents ortreatments.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes,separate pills or capsules, or separate infusions. In general, duringalternation therapy, an effective dosage of each active ingredient isadministered sequentially, i.e., serially, whereas in combinationtherapy, effective dosages of two or more active ingredients areadministered together.

In a particular embodiment of therapy, a compound of Formula I, or astereoisomer, tautomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, may be combined with othertherapeutic, hormonal or antibody agents such as those described herein,as well as combined with surgical therapy and radiotherapy. Combinationtherapies according to the present invention thus comprise theadministration of at least one compound of Formula I, or a stereoisomer,tautomer, solvate, metabolite, or pharmaceutically acceptable salt orprodrug thereof, and the use of at least one other cancer treatmentmethod. The amounts of the compound(s) of Formula I and the otherpharmaceutically active therapeutic agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect.

Metabolites of Compounds of Formula I

Also falling within the scope of this invention are the in vivometabolic products of Formula I described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound. Accordingly, the inventionincludes metabolites of compounds of Formula I, including compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the diseases anddisorders described above is provided. In one embodiment, the kitcomprises a container comprising a compound of Formula I, or astereoisomer, tautomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof. The kit may further comprise a labelor package insert on or associated with the container. The term “packageinsert” is used to refer to instructions customarily included incommercial packages of therapeutic products, that contain informationabout the indications, usage, dosage, administration, contraindicationsand/or warnings concerning the use of such therapeutic products.Suitable containers include, for example, bottles, vials, syringes,blister pack, etc. The container may be formed from a variety ofmaterials such as glass or plastic. The container may hold a compound ofFormula I or a formulation thereof which is effective for treating thecondition and may have a sterile access port (for example, the containermay be an intravenous solution bag or a vial having a stopper pierceableby a hypodermic injection needle). At least one active agent in thecomposition is a compound of Formula I. The label or package insertindicates that the composition is used for treating the condition ofchoice, such as cancer. In addition, the label or package insert mayindicate that the patient to be treated is one having a disorder such asa hyperproliferative disorder, neurodegeneration, cardiac hypertrophy,pain, migraine or a neurotraumatic disease or event. In one embodiment,the label or package inserts indicates that the composition comprising acompound of Formula I can be used to treat a disorder resulting fromabnormal cell growth. The label or package insert may also indicate thatthe composition can be used to treat other disorders. Alternatively, oradditionally, the article of manufacture may further comprise a secondcontainer comprising a pharmaceutically acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of thecompound of Formula I and, if present, the second pharmaceuticalformulation. For example, if the kit comprises a first compositioncomprising a compound of Formula I and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I, such as tablets or capsules. Sucha kit preferably includes a number of unit dosages. Such kits caninclude a card having the dosages oriented in the order of theirintended use. An example of such a kit is a “blister pack”. Blisterpacks are well known in the packaging industry and are widely used forpackaging pharmaceutical unit dosage forms. If desired, a memory aid canbe provided, for example in the form of numbers, letters, or othermarkings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

According to one embodiment, a kit may comprise (a) a first containerwith a compound of Formula I contained therein; and optionally (b) asecond container with a second pharmaceutical formulation containedtherein, wherein the second pharmaceutical formulation comprises asecond compound with anti-hyperproliferative activity. Alternatively, oradditionally, the kit may further comprise a third container comprisinga pharmaceutically-acceptable buffer, such as bacteriostatic water forinjection (BWFI), phosphate-buffered saline, Ringer's solution anddextrose solution. It may further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, needles, and syringes.

In certain other embodiments wherein the kit comprises a composition ofFormula I and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

Preparation of Formula I Compounds

Compounds of Formula I may be synthesized by synthetic routes thatinclude processes analogous to those well-known in the chemical arts,particularly in light of the description contained herein, and those forother heterocycles described in: Comprehensive Heterocyclic ChemistryII, Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; LiebigsAnnalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta,41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990), eachof which are expressly incorporated by reference. Starting materials aregenerally available from commercial sources such as Aldrich Chemicals(Milwaukee, Wis.) or are readily prepared using methods well known tothose skilled in the art (e.g., prepared by methods generally describedin Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch derorganischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, includingsupplements (also available via the Beilstein online database).

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing Formula I compoundsand necessary reagents and intermediates are known in the art andinclude, for example, those described in R. Larock, ComprehensiveOrganic Transformations, VCH Publishers (1989); T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wileyand Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995) and subsequent editionsthereof.

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, for example 5 to 1,000 compounds, or 10 to 100compounds. Libraries of compounds of Formula I may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesesusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art. Thus according to a further aspect ofthe invention there is provided a compound library comprising at least 2compounds, or pharmaceutically acceptable salts thereof.

The Figures and Examples provide exemplary methods for preparing FormulaI compounds. Those skilled in the art will appreciate that othersynthetic routes may be used to synthesize the Formula I compounds.Although specific starting materials and reagents are depicted anddiscussed in the Figures and Examples, other starting materials andreagents can be easily substituted to provide a variety of derivativesand/or reaction conditions. In addition, many of the exemplary compoundsprepared by the described methods can be further modified in light ofthis disclosure using conventional chemistry well known to those skilledin the art.

In preparing compounds of Formulas I, protection of remote functionality(e.g., primary or secondary amine) of intermediates may be necessary.The need for such protection will vary depending on the nature of theremote functionality and the conditions of the preparation methods.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, 1991.

General Preparative Procedures

The Suzuki-type coupling reaction is useful to form carbon-carbon bondsto attach the rings of Formula I compounds and intermediates such as A-3(Suzuki (1991) Pure Appl. Chem. 63:419-422; Miyaura and Suzuki (1979)Chem. Reviews 95(7):2457-2483; Suzuki (1999) J. Organometal. Chem.576:147-168). Suzuki coupling is a palladium mediated cross couplingreaction of an arylhalide, such as B-2 or B-5, with a boronic acid suchas A-1 or A-2. For example, B-2 may be combined with about 1.5equivalents of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane), anddissolved in about 3 equivalents of sodium carbonate as a 1 molarsolution in water and an equal volume of acetonitrile. A catalyticamount, or more, of a low valent palladium reagent, such asbis(triphenylphosphine)palladium(II) dichloride, is added. In some casespotassium acetate is used in place of sodium carbonate to adjust the pHof the aqueous layer. The reaction is then heated to about 140-150° C.under pressure in a microwave reactor such as the Biotage Optimizer(Biotage, Inc.) for 10 to 30 minutes. The contents are extracted withethyl acetate, or another organic solvent. After evaporation of theorganic layer the boron ester A-1 may be purified on silica or byreverse phase HPLC. Substituents Y¹, Y², R⁵ and R⁶ are as defined, orprotected forms or precursors thereof. Likewise, bromide intermediateB-5 can be boronylated to give A-2. Substituents Y¹, Y², R¹, R², R³, R⁴,Z¹, Z², Z³, Z⁴, and X are as defined, or protected forms or precursorsthereof.

Suzuki coupling of B-2 and A-2, or of A-1 and B-5, gives Formula Icompound or intermediate A-3. Boronic ester (or acid) (1.5 eq) A-1 orA-2, and a palladium catalyst such asbis(triphenylphosphine)palladium(II) chloride (0.05 eq) is added to amixture of halo intermediate (1 eq) B-2 or B-5 in acetonitrile and 1 Mof sodium carbonate aqueous solution (equal volume as acetonitrile). Thereaction mixture is heated to about 150° C. in a microwave for about 15min. LC/MS indicates when the reaction is complete. Water is added tothe mixture, and the precipitated product is filtered and purified byHPLC to yield the product A-3. Substituents R^(1′), R^(2′), R^(4′) maybe R¹, R², R⁴ as defined, or protected forms or precursors thereof.

A variety of palladium catalysts can be used during the Suzuki couplingstep. Various low valent, Pd(II) and Pd(0) catalysts may be used in theSuzuki coupling reaction, including PdCl2(PPh₃)₂, Pd(t-Bu)₃, PdCl₂ dppfCH₂Cl₂, Pd(PPh₃)₄, Pd(OAc)/PPh₃, Cl₂Pd[(Pet₃)]₂, Pd(DIPHOS)₂,Cl₂Pd(Bipy), [PdCl(Ph₂PCH₂PPh₂)]₂, Cl₂Pd[P(o-tol)₃]₂,Pd₂(dba)₃/P(o-tol)₃, Pd₂(dba)/P(furyl)₃, Cl₂Pd[P(furyl)₃]₂,Cl₂Pd(PMePh₂)₂, Cl₂Pd[P(4-F-Ph)₃]₂, Cl₂Pd[P(C₆F₆)₃]₂,Cl₂Pd[P(2-COOH-Ph)(Ph)₂]₂, Cl₂Pd[P(4-COOH-Ph)(Ph)₂]₂, and encapsulatedcatalysts Pd EnCat™ 30, Pd EnCat™ TPP30, and Pd(II)EnCat™ BINAP30 (US2004/0254066).

The Buchwald reaction is useful to aminate 6-bromo intermediates B-1(Wolf and Buchwald (2004) Org. Synth Coll. Vol. 10:423; Paul et al(1994) Jour. Amer. Chem. Soc. 116:5969-5970). To a solution of halointermediate B-1 in DMF is added the appropriate amine R⁵—NH₂ (200 mol%), Cs₂CO₃ (50 mol %), Pd₂(dba)₃ (5 mol %), and XANTPHOS (10 mol %). Thereaction is heated to about 110° C. under pressure in a Biotageoptimizer microwave reactor for about 30 min. The resulting solution isconcentrated in vacuo to give B-2. Other palladium catalysts andphosphine ligands may be useful.

N-Aryl amide intermediates B-5 can also be prepared under Buchwaldconditions with cyclic amide intermediates B-3 and aryl bromides B-4.

FIG. 1 shows an exemplary synthetic route to prepare 6-chloro,4-aminopyridazinone compounds, including6-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one101f, from 3-nitropyrazole-5-carboxylic acid.

FIG. 2 shows an exemplary synthetic route to a tricyclic amide-phenylboronate compounds, including2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one101m, from 4,5,6,7-tetrahydro-1H-indole.

FIG. 3 shows an exemplary synthetic route to tricyclic amide-phenylbromide compounds, including2-bromo-6-(1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzylacetate 104h, from 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylicacid.

FIG. 4 shows another exemplary synthetic route to tricyclic amide-phenylbromide compounds, including6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-one105i, from 3-methylcyclopent-2-enone.

FIG. 5 shows an exemplary synthetic route to tricyclic1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-onecompounds as boronate esters, including2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 118f from 5,6,7,8-tetrahydroindolizine-2-carboxylic acid.

FIG. 6 shows an exemplary synthetic route to intermediate2-Bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 198d from 1,3-dibromo-5-fluoro-2-iodobenzene.

FIG. 7 shows an exemplary synthetic route to intermediate4-Fluoro-2-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 198g.

FIG. 8 shows an exemplary synthetic route to intermediate5-Fluoro-2-(1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 210e.

FIG. 9 shows an exemplary synthetic route to intermediate5-[5-fluoro-2-(acetoxymethyl)-3-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one212c.

Methods of Separation

In the methods of preparing Formula I compounds, it may be advantageousto separate reaction products from one another and/or from startingmaterials. The desired products of each step or series of steps isseparated and/or purified to the desired degree of homogeneity by thetechniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like. Selection of appropriate methodsof separation depends on the nature of the materials involved, such as,boiling point and molecular weight in distillation and sublimation,presence or absence of polar functional groups in chromatography,stability of materials in acidic and basic media in multiphaseextraction, and the like.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob I I I. J. Org. Chem.(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

EXAMPLES Example 1012-(2-methyl-3-(5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one101 Example 101a (3-Nitro-1H-pyrazol-5-yl)methanol 101a

A 3-L three-neck round-bottomed flask equipped with a mechanicalstirrer, addition funnel and nitrogen inlet was purged with nitrogen andcharged with 3-nitropyrazole-5-carboxylic acid (28.0 g, 178 mmol) andTHF (420 mL) and cooled to −5° C. using an ice/acetone bath. Borane-THFcomplex solution (1.0 M, 535 mL, 535 mmol) was added at a rate thatmaintained the internal reaction temperature below 5° C. After theaddition was complete the cooling bath was removed and the reaction wasstirred at room temperature for 18 h. After this time the reaction wascooled to −5° C. using an ice/acetone bath, water (70 mL) and 4Nhydrochloric acid (70 mL) was added and the reaction was stirred atreflux for 1 h in order to destroy the borane complex with pyrazole. Thereaction was cooled to room temperature and concentrated under reducedpressure to a volume of approximately 30 mL. Ethyl acetate (175 mL) wasadded and the mixture stirred for 15 min. The aqueous layer wasseparated and extracted with ethyl acetate (4×200 mL). The combinedorganic layers were washed with saturated aqueous sodium bicarbonate(2×50 mL), brine (50 mL) and dried over sodium sulfate, the drying agentwas removed by filtration, and the filtrate concentrated under reducedpressure to afford 101a in a 94% yield (24.0 g) as a light yellow solid:¹H NMR (300 MHz, DMSO-d₆) δ 13.90 (br s, 1H), 6.87 (s, 1H), 5.58 (t, 1H,J=5.4 Hz), 4.53 (d, 2H, J=5.1 Hz); MS (ESI+) m/z 144.0 (M+H)

Example 101b (1-(2-Bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol 101b

A 1-L three-necked round-bottomed flask equipped with a mechanicalstirrer and thermoregulator was purged with nitrogen and charged with(3-nitro-1H-pyrazol-5-yl)methanol 101a (25.0 g, 175 mmol), DMF (250 mL),and cesium carbonate (70.0 g, 215 mmol) was heated at 104° C. for 5 min.The reaction mixture was then cooled to 0° C. using an ice/acetone bathand dibromoethane (329 g, 1.75 mol) was added portionwise (no exotherm).The reaction was stirred at 0° C. for 1 then at room temperature for 4h. After this time a solution of KH₂PO4 (40 g) in water (400 mL) wasadded slowly. The reaction mixture stirred at room temperature for 30min. Ethyl acetate (450 mL) was added and the aqueous layer wasseparated and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with water (200 mL), brine (200 mL), driedover sodium sulfate, and the drying agent was removed by filtration. Thefiltrate was concentrated under reduced pressure to afford an 86% yield(37.5 g) of crude 101b as an orange oil: ¹H NMR (300 MHz, CDCl₃) δ 6.85(s, 1H), 4.82 (d, 2H, J=5.4 Hz), 4.66 (t, 2H, J=6.3 Hz), 3.83 (t, 2H,J=6.3 Hz); MS (ESI+) m/z 249.9 (M+H).

Example 101c 1-(2-Bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 101c

A 500-mL three-necked round-bottomed flask equipped with a magneticstirrer, nitrogen inlet and reflux condenser was purged with nitrogenand charged with (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol 101b(37.0 g, 148 mmol) and chloroform (160 mL). The reaction was cooled to−5° C. using an ice/acetone bath and phosphorous tribromide (40.0 g, 148mmol) was added portionwise. The cooling bath was removed and thereaction stirred at reflux for 2 h. After this time, the reaction wascooled to −5° C. and saturated aqueous sodium bicarbonate (250 mL) wasadded until a pH of 8.5 was reached. The mixture was extracted withethyl acetate (3×150 mL) and the combined organic layers were washedwith saturated aqueous sodium carbonate (2×50 mL), brine (75 mL), driedover sodium sulfate and the drying agent was removed by filtration. Thefiltrate was concentrated under reduced pressure to afford a yellowresidue that was dissolved with gentle heating in methylene chloride (60mL). Hexanes (approximately 20 mL) was added and the solution becamecloudy. The mixture was heated until a solid precipitate formed,methylene chloride (9 mL) was added and the solution became clear. Thesolution was left to cool to room temperature and after 4 h theresulting crystals were collected by vacuum filtration. The filter cakewas washed with a ice cold 1:2 mixture of methylene chloride:hexanes(2×20 mL) to afford 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole(19.7 g). The combined filtrates were evaporated and the procedure wasperformed again to afford an additional 9.70 g of1-(2-bromoethyl)-5-(bromo-methyl)-3-nitro-1H-pyrazole. The solids werecombined and dried under high vacuum for 18 h to afford a 57% yield(26.0 g) of 101c as white crystals: mp 95-97° C.; ¹H NMR (300 MHz,CDCl₃) δ 6.93 (s, 1H), 4.63 (t, 2H, J=6.0 Hz), 4.54 (s, 2H), 3.86 (t,2H, J=6.0 Hz).

Example 101d 5-Methyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine101d

A 1-L single-neck round-bottomed flask equipped with a magnetic stirrerand nitrogen inlet was charged with THF (350 mL), 101c (10.0 g, 32.2mmol), 2M methylamine solution in THF (113 mL, 225 mmol) and stirred atroom temperature for 72 h. After this time the reaction was concentratedto dryness under reduced pressure, and the resulting solid was stirredwith a mixture of ethyl acetate (75 mL) and 10% aqueous potassiumcarbonate (75 mL). The aqueous layer was separated and extracted withethyl acetate (2×75 mL). The combined organic extracts were washed with10% aqueous potassium carbonate (75 mL), followed by brine (50 mL) anddried over sodium sulfate. The drying agent was removed by filtration,and the filtrate concentrated under reduced pressure to afford 101d in97% yield (5.70 g) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 6.62 (s,1H), 4.28 (t, 2H, J=5.4 Hz), 3.67 (s, 2H), 2.95 (t, 2H, J=5.4 Hz), 2.52(s, 3H); MS (ESI+) m/z 183.0 (M+H)

Example 101e 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine101e

A 500-mL Parr reactor bottle was purged with nitrogen and charged with10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of5-methyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 101d (4.00 g,2.20 mmol) in ethanol (160 mL). The bottle was attached to Parrhydrogenator, evacuated, charged with hydrogen gas to a pressure of 45psi and shaken for 2 h. After this time, the hydrogen was evacuated, andnitrogen was charged into the bottle. Celite 521 (1.0 g) was added, andthe mixture was filtered through a pad of Celite 521. The filter cakewas washed with ethanol (2×75 mL), and the combined filtrates wereconcentrated to dryness under reduced pressure to afford a 99% yield of101e (3.31 g) as an orange solid: ¹H NMR (300 MHz, CDCl₃) δ 5.34 (s,1H), 3.98 (t, 2H, J=5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, J=5.7 Hz), 2.45(s, 3H); MS (ESI+) m/z 153.1 (M+H)

Example 101f6-Chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one101f

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and nitrogen inlet was charged with1,4-dioxane (5.0 mL), 101e (152 mg, 1.00 mmol),4-bromo-6-chloropyridazin-3(2H)-one (209 mg, 1.00 mmol) and a 1 M THFsolution of LiHMDS (5.0 mL, 5.00 mmol). After bubbling nitrogen throughthe resulting solution for 30 min, Xantphos (49 mg, 0.05 mmol) andtris(dibenzylideneacetone)dipalladium(0) (59 mg, 0.085 mmol) were added,and the reaction mixture was heated at reflux for 3 h. After this time,the reaction was cooled to room temperature, and water (10 mL) wasadded. The pH was adjusted to 6.5 with 2 N hydrochloric acid. Theresulting precipitate was collected by vacuum filtration, washed withwater (2×25 mL), absorbed on silica gel and purified by flashchromatography to afford a 74% yield (210 mg) of 101f as a light brownsolid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.94 (s, 1H), 9.55 (s, 1H), 7.68 (s,1H), 5.96 (s, 1H), 4.04 (t, 1H, J=5.7 Hz), 3.53 (s, 2H), 2.82 (t, 2H,J=5.7 Hz), 2.36 (s, 3H); MS (ESI+) m/z 281.1 (M+H)

Example 101g2,2,2-Trichloro-1-(4,5,6,7-tetrahydro-1H-indol-2-yl)ethanone 101g

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer, condenser and nitrogen inlet was purged with nitrogen andcharged with 4,5,6,7-tetrahydro-1H-indole (3.00 g, 24.8 mmol),trichloroacetyl chloride (13.5 g, 74.4 mmol) and 1,2-dichloroethane (50mL). The solution was stirred at 85° C. for 2 h. After that time, thereaction mixture was concentrated under reduced pressure to afford a100% yield (6.50 g) of 101g as a black semi-solid: ¹H NMR (500 MHz,DMSO-d₆) δ 11.94 (s, 1H), 7.05 (s, 1H), 2.62 (t, 2H, J=6.0 Hz), 2.47 (t,2H, J=6.0 Hz), 1.80 (m, 2H), 1.65 (m, 2H); MS (ESI+) m/z 266.0 (M+H)

Example 101h Ethyl 4,5,6,7-Tetrahydro-1H-indole-2-carboxylate 101h

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was purged with nitrogen and charged with101g (6.50 g, 24.8 mmol), sodium ethoxide (17.0 mg, 0.25 mmol) andethanol (40 mL). The solution was stirred at room temperature for 1 h.After that time, the reaction mixture was concentrated under reducedpressure. The residue was purified by column chromatography to afford a100% yield (4.80 g) of 101h as a brown solid: mp 70-72° C.; ¹H NMR (300MHz, CDCl₃) δ 9.08 (s, 1H), 6.75 (s, 1H), 4.25 (q, 2H, J=7.2 Hz), 2.65(t, 2H, J=6.0 Hz), 2.56 (t, 2H, J=6.0 Hz), 1.85 (m, 4H), 1.28 (t, 3H,J=7.2 Hz); MS (ESI+) m/z 194.1 (M+H)

Example 101i Ethyl1-(Cyanomethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101i

A 125-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was purged with nitrogen and charged with101h (5.76 g, 29.8 mmol) and DMF (50 mL). The solution was cooled to 0°C. using an ice bath. NaH (60% dispersion in mineral oil, 1.43 g, 35.8mmol) was added. The resulting mixture was stirred at room temperaturefor 1 h. After that time, bromoacetonitrile (1.43 g, 35.8 mmol) wasadded. The mixture was stirred at room temperature for 14 h. After thattime, the reaction mixture was concentrated under reduced pressure andthe residue was partitioned between ethyl acetate (150 mL) and water(450 mL). The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate (3×150 mL). The combined organic layerswere washed with brine, dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatography toafford a 55% yield (3.80 g) of ethyl1-(cyanomethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101i as ayellow semi-solid: ¹H NMR (300 MHz, CDCl₃) δ 6.66 (s, 1H), 5.29 (s, 2H),4.28 (q, 2H, J=7.2 Hz), 2.62 (t, 2H, J=6.3 Hz), 2.49 (t, 2H, J=6.3 Hz),1.92 (m, 2H), 1.75 (m, 2H), 1.33 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 233.1(M+H).

Example 101j Ethyl1-(2-Aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101j

A 200-mL Parr reactor bottle was purged with nitrogen and charged with10% palladium on carbon (50% wet, 1.28 g dry weight), ethyl1-(cyanomethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101i (3.00 g,12.9 mmol), 12% hydrochloric acid (6.5 mL, 25 mmol), ethyl acetate (60mL) and ethanol (40 mL). The bottle was attached to a Parr hydrogenator,evacuated, charged with hydrogen gas to a pressure of 50 psi and shakenfor 6 h. After this time, the hydrogen was evacuated, and nitrogen wascharged into the bottle. Celite 521 (4.0 g) was added, and the mixturewas filtered through a pad of Celite 521. The filter cake was washedwith ethanol (2×20 mL), and the combined filtrates were concentrated todryness under reduced pressure. The residue was partitioned betweenethyl acetate (150 mL) and 10% aqueous potassium carbonate (100 mL). Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (3×75 mL). The combined organic layers were dried oversodium sulfate and concentrated under reduced pressure. The residue wastriturated with ethanol (5 mL) to afford a 71% yield (1.71 g) of ethyl1-(2-aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101j as awhite solid: mp 102-104° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 6.61 (s, 1H),6.22 (br, 2H), 4.15 (m, 4H), 2.77 (m, 2H), 2.59 (t, 2H, J=6.5 Hz), 2.42(t, 2H, J=6.5 Hz), 1.70 (m, 2H), 1.62 (m, 2H), 1.23 (t, 3H, J=7.0 Hz);MS (APCI+) m/z 237.2 (M+H)

Example 101k Ethyl1-(2-Aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101k

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was purged with nitrogen and charged withethyl 1-(2-aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101j(1.80 g, 7.63 mmol), sodium ethoxide (1.55 g, 22.8 mmol) and ethanol (50mL). The mixture was stirred at 55° C. for 5 h. After that time, thereaction mixture was concentrated under reduced pressure and the residuewas partitioned between ethyl acetate (200 mL) and water (100 mL). Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (2×100 mL). The combined organic layers were washed withbrine, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography to afford a42% yield (605 mg) of ethyl1-(2-aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101k as awhite solid: mp 207-209° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.41 (s, 1H),6.36 (s, 1H), 3.84 (t, 2H, J=6.0 Hz), 3.42 (m, 2H), 2.51 (t, 2H, J=6.0Hz), 2.42 (t, 2H, J=6.0 Hz), 1.76 (m, 2H), 1.65 (m, 2H); (APCI+) m/z191.3 (M+H)

Example 101l2-(3-Bromo-2-methylphenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one101l

A 50-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with ethyl1-(2-aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101k (560 mg, 2.95 mmol), 2,6-dibromotoluene (1.47 g, cesium carbonate (1.92 g,5.90 mmol), N,N′-dimethylethylenediamine (260 mg, 2.95 mmol) and1,4-dioxane (25 mL). After bubbling nitrogen through the resultingsuspension for 30 min, copper N,N′-dimethylethylenediamine (260 mg, 2.95mmol) was added, and the reaction mixture was heated at 105° C. (oilbath temperature) for 14 h. After this time, the mixture was cooled toroom temperature and filtered. The filtrate was diluted with ethylacetate (100 mL) and water (20 mL). The organic layer was separated, andthe aqueous layer was extracted with ethyl acetate (3×30 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography to afford a 57% yield (600 mg) of2-(3-bromo-2-methylphenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one101l as a white solid: mp 163-165° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.57(dd, 1H, J=8.0, 0.5 Hz), 7.32 (d, 1H, J=7.5 Hz), 7.21 (t, 1H, J=8.0 Hz),6.50 (s, 1H), 4.11 (m, 3H), 3.75 (m, 1H), 2.59 (m, 2H), 2.45 (m, 2H),2.21 (s, 3H), 1.78 (m, 2H), 1.68 (m, 2H); (APCI+) m/z 358.6 (M+H)

Example 101m2-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one101m

A 50-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with of2-(3-bromo-2-methylphenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one101l (600 mg, 1.67 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (1.70 g, 6.70mmol), potassium acetate (656 mg, 6.68 mmol), and 1,4-dioxane (25 mL).After bubbling nitrogen through the resulting suspension for 30 min,XPhos (159 mg, 0.334 mmol) and tris(dibenzylideneacetone)dipalladium(0)(153 mg, 0.167 mmol) were added, and the reaction mixture was heated at105° C. (oil bath temperature) for 14 h. After this time, the mixturewas cooled to room temperature and filtered. The filtrate was dilutedwith ethyl acetate (75 mL) and water (20 mL). The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate (3×25mL). The combined organic layers were dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography to afford a 109% crude yield (740 mg) of2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one101m as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.75 (dd, 1H, J=6.6, 2.1Hz), 7.26 (m, 2H), 6.80 (s, 1H), 4.10 (m, 3H), 3.75 (m, 1H), 2.54 (m,4H), 2.45 (s, 3H), 1.87 (m, 2H), 1.75 (m, 2H), 1.25 (s, 12H); MS (APCI+)m/z 407.7 (M+H)

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one101m (740 mg, 1.67 mmol),6-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one101f (422 mg, 1.34 mmol), sodium carbonate (568 mg, 5.36 mmol), DMF (5mL), water (5 mL) and 1,4-dioxane (20 mL). After bubbling nitrogenthrough the resulting suspension for 30 min,tetrakis(triphenylphosphine)palladium(0) (155 mg, 0.134 mmol) was added,and the reaction mixture was heated at 100° C. for 15 h. After thistime, the mixture was cooled to room temperature and diluted with ethylacetate (100 mL) and water (30 mL). The organic layer was separated, andthe aqueous layer was extracted with ethyl acetate (3×25 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel to afford a 17% yield (120 mg) of 101 as anoff-white solid: mp 195-197° C.; ¹H NMR (500 MHz, DMSO-d₆) d 12.95 (s,1H), 9.19 (s, 1H), 7.75 (s, 1H), 7.34 (m, 2H), 7.29 (m, 1H), 6.50 (s,1H), 5.96 (s, 1H), 4.14 (m, 1H), 4.08 (m, 2H), 3.95 (m, 2H), 3.77 (m,1H), 3.51 (s, 2H), 2.78 (t, 2H, J=6.0 Hz), 2.60 (m, 2H), 2.46 (t, 2H,J=6.0 Hz), 2.35 (s, 3H), 2.07 (s, 3H), 1.78 (m, 2H), 1.68 (m, 2H); MS(ESI+) m/z 521 (M+H).

Example 1022-(2-methyl-3-(5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one102 Example 102a Ethyl 1-(Cyanomethyl)-1H-indole-2-carboxylate 102a

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was purged with nitrogen and charged withethyl indole-2-carboxylate (10.0 g, 52.9 mmol) and DMF (100 mL). Thesolution was cooled to 0° C. using an ice bath. NaH (60% dispersion inmineral oil, 2.54 g, 63.5 mmol) was added. The resulting mixture wasstirred at room temperature for 1 h. After that time, bromoacetonitrile(7.62 g, 63.5 mmol) was added. The mixture was stirred at roomtemperature for 14 h. After that time, the reaction mixture wasconcentrated under reduced pressure and the residue was partitionedbetween ethyl acetate (300 mL) and water (900 mL). The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate (3×300mL). The combined organic layers were washed with brine, dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography to afford a 66% yield (8.00 g) of 102aas an off-white solid: mp 65-67° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.72 (d,1H, J=8.1), 7.44 (m, 3H), 7.25 (m, 1H), 5.62 (s, 2H), 4.42 (q, 2H, J=7.2Hz), 1.43 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 229.1 (M+H).

Example 102b 3,4-Dihydropyrazino[1,2-a]indol-1(2H)-one 102b

A 500-mL Parr reactor bottle was purged with nitrogen and charged with10% palladium on carbon (50% wet, 3.47 g dry weight), 102a (8.00 g, 35.0mmol), 12% hydrochloric acid (17.5 mL, 70 mmol), ethyl acetate (150 mL)and ethanol (100 mL). The bottle was attached to a Parr hydrogenator,evacuated, charged with hydrogen gas to a pressure of 50 psi and shakenfor 6 h. After this time, the hydrogen was evacuated, and nitrogen wascharged into the bottle. Celite 521 (10.0 g) was added, and the mixturewas filtered through a pad of Celite 521. The filter cake was washedwith ethanol (2×50 mL), and the combined filtrates were concentrated todryness under reduced pressure. The residue was partitioned betweenethyl acetate (400 mL) and 10% aqueous potassium carbonate (300 mL). Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (3×200 mL). The combined organic layers were dried oversodium sulfate and concentrated under reduced pressure. The residue wastriturated with ethanol (5 mL) to afford a 70% yield (4.57 g) of 102b asan off-white solid: mp 228-230° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d,1H, J=8.1 Hz), 7.34 (m, 3H), 7.18 (m, 1H), 6.75 (br s, 1H), 4.29 (t, 2H,J=5.4 Hz), 3.84 (m, 2H); MS (ESI+) m/z 187.1 (M+H).

Example 102c2-(3-Bromo-2-methylphenyl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one102c

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 102b(1.00 g, 5.37 mmol), (2.69 g, 10.7 mmol), cesium carbonate (3.49 g, 10.7mmol), N,N′-dimethylethylenediamine (473 mg, 5.37 mmol) and 1,4-dioxane(45 mL). After bubbling nitrogen through the resulting suspension for 30min, copper iodide (510 mg, 2.69 mmol) was added, and the reactionmixture was heated at 105° C. (oil bath temperature) for 14 h. Afterthis time, the mixture was cooled to room temperature and filtered. Thefiltrate was diluted with ethyl acetate (200 mL) and water (40 mL). Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (3×50 mL). The combined organic layers were dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography to afford a 62% yield (1.18 g) of 102cas an off-white solid: mp 178-180° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.74(dt, 1H, J=8.2, 1.0 Hz), 7.58 (dd, 1H, J=7.8, 1.2 Hz), 7.37 (m, 3H),7.19 (m, 3H), 4.45 (m, 2H), 4.21 (m, 1H), 3.95 (m, 1H), 2.38 (s, 3H); MS(ESI+) m/z 355.0 (M+H).

Example 102d2-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one102d

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 102c(1.18 g, 3.32 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (929 mg,3.65 mmol), potassium acetate (491 mg, 4.98 mmol) and 1,4-dioxane (25mL). After bubbling nitrogen through the resulting suspension for 30min, XPhos (317 mg, 0.664 mmol) andtris(dibenzylideneacetone)-dipalladium(0) (561 mg, 0.332 mmol) wereadded, and the reaction mixture was heated at 105° C. (oil bathtemperature) for 14 h. After this time, the mixture was cooled to roomtemperature and filtered. The filtrate was diluted with ethyl acetate(150 mL) and water (40 mL). The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chroma-tography toafford a 57% yield (760 mg) of 102d as an off-white solid: mp 193-195°C.; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (dd, 1H, J=7.0, 1.7 Hz), 7.74 (d, 1H,J=8.2 Hz), 7.37 (m, 3H), 7.28 (m, 2H), 7.19 (m, 1H), 4.45 (m, 2H), 4.22(m, 1H), 3.94 (m, 1H), 2.50 (s, 3H), 1.35 (s, 12H); MS (ESI+) m/z 403.2(M+H).

A 25-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 102d(760 mg, 1.89 mmol), 101f (379 mg, 1.35 mmol), sodium carbonate (430 mg,4.05 mmol), DMF (5 mL), water (2.5 mL) and 1,4-dioxane (8 mL). Afterbubbling nitrogen through the resulting suspension for 30 min,tetrakis(triphenylphosphine)palladium(0) (437 mg, 0.378 mmol) was added,and the reaction mixture was heated at reflux for 14 h. After this time,the mixture was cooled to room temperature and diluted with ethylacetate (100 mL) and water (30 mL). The organic layer was separated, andthe aqueous layer was extracted with ethyl acetate (3×25 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica to afford a 26% yield (183 mg) of 102 as anoff-white solid: mp 188-190° C. (dec); ¹H NMR (300 MHz, DMSO-d₆) δ 12.99(s, 1H), 9.23 (s, 1H), 7.79 (s, 1H), 7.71 (d, 1H, J=8.1 Hz), 7.61 (d,1H, J=7.9 Hz), 7.38 (m, 4H), 7.14 (m, 2H), 5.97 (s, 1H), 4.63 (m, 1H),4.49 (m, 1H), 4.27 (m, 1H), 4.12 (m, 3H), 3.51 (s, 2H), 2.79 (t, 2H,J=5.1 Hz), 2.35 (s, 3H), 2.18 (s, 3H); MS (ESI+) m/z 525 (M+H).

Example 1034-{2-Methyl-3-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phenyl}-7-thia-4-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6),9,11-tetraen-5-one103 Example 103a Methyl 3-(Bromomethyl)benzo[b]thiophene-2-carboxylate103a

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer, nitrogen inlet and reflux condenser was purged with nitrogenand charged with methyl 3-methylbenzo[b]thiophene-2-carboxylate (2.00 g,9.70 mmol) and benzene (20 mL). N-bromosuccinimide (1.72 g, 9.70 mmol)and 2,2′-azobisisobutyronitrile (160 mg, 1.00 mmol) were added, and themixture was refluxed for 2 h. After this time, the mixture was cooled toroom temperature and filtered. The filter cake was rinsed with carbontetrachloride (20 mL) and the filtrate was concentrated under reducedpressure. The resulting residue was purified by column chromatography toafford 103a in 82% yield (2.27 g) as a white solid: mp 101-102° C.; ¹HNMR (500 MHz, CDCl₃) δ 7.97 (m, 1H), 7.86 (m, 1H), 7.51 (m, 2H), 5.22(s, 2H), 3.97 (s, 3H).

Example 103b3-((3-Bromo-2-methylphenylamino)methyl)benzo[b]thiophene-2-carboxylicAcid 103b

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with103a (2.26 g, 7.92 mmol), 3-bromo-2-methylaniline (1.77 g, 9.51 mmol)and acetonitrile (50 mL). Cesium carbonate (7.75 g, 23.8 mmol) wasadded, and the mixture was stirred at 50° C. for 14 h. After this time,the reaction mixture was concentrated under reduced pressure and theresulting residue was dissolved in THF (15 mL), methanol (15 mL) andwater (15 mL) and treated with lithium hydroxide monohydrate (1.30 g,31.0 mmol). After stirring at room temperature for 14 h, the solvent wasremoved under reduced pressure and the resulting residue was acidifiedwith 2 M hydrochloric acid to pH 5. The resulting mixture was extractedwith ethyl acetate (3×30 mL), and the organic extracts were combined anddried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography toafford 103b in 59% yield (1.70 g) as a white solid: mp 120-121° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 8.30 (d, 1H, J=12.5 Hz), 7.98 (d, 1H, J=12.5Hz), 7.46 (m, 2H), 6.77 (m, 3H), 4.97 (s, 2H), 2.15 (s, 3H); MS (ESI+)m/z 378.9 (M+H).

Example 103c2-((3-Bromo-2-methylphenyl)-1Hbenzothieno[2,3-c]pyrrol-3(2H)-one 103c

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 103b (1.70 g, 4.51mmol), triethylamine (914 mg, 9.00 mmol) and anhydrous DMF (25 mL).Benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphoniumhexafluorophosphate (BOP, 2.60 g, 5.90 mmol) was added, and the reactionwas stirred at room temperature for 14 h. After this time, the reactionwas diluted with water (20 mL), and the resulting suspension wasfiltered. The filter cake was dissolved in methylene chloride (40 mL),and the solution was washed with saturated aqueous sodium bicarbonate(10 mL), water (10 mL), and dried over sodium sulfate. The drying agentwas removed by filtration, and the solvent was evaporated under reducedpressure. The resulting residue was purified by flash chromatography toafford a 78% yield of 103c (1.26 g) as a white semi-solid: ¹H NMR (500MHz, CDCl₃) δ 7.97 (m, 1H), 7.80 (m, 1H), 7.60 (d, 1H, J=8.0 Hz), 7.49(m, 2H), 7.28 (d, 1H, J=8.0 Hz), 7.16 (t, 1H, J=8.0 Hz), 4.85 (s, 2H),2.37 (s, 3H).

Example 103d2-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-benzothieno[2,3-c]pyrrol-3(2H)-one103d

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with103c (1.26 g, 3.51 mmol),4,4,4′,4′-5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (2.23 g, 8.80mmol), potassium acetate (1.00 g, 10.20 mmol) and 1,4-dioxane (30 mL). Astream of nitrogen was passed through the resulting suspension for 30min. [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (260mg, 0.355 mmol) was added, and the reaction was stirred at reflux for 3h. After this time, the mixture was cooled to ambient temperature,partitioned between water (25 mL) and ethyl acetate (50 mL) and filteredthrough a plug of Celite 521. The organic phase was separated, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by flash chromatography to affordquantitative yield (1.84 g) of 103d as a yellow semi-solid: ¹H NMR (500MHz, CDCl₃) d 7.97 (m, 1H), 7.80 (m, 2H), 7.47 (m, 2H), 7.35 (d, 1H,J=7.5 Hz), 7.28 (d, 1H, J=7.5 Hz), 4.86 (s, 2H), 2.48 (s, 3H), 1.35 (s,12H).

Example 103e 4-Bromo-6-chloro-2-methylpyridazin-3(2H)-one 103e

A 250-mL single-necked round bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with4-bromo-6-chloropyridazin-3(2H)-one (1.00 g, 4.77 mmol) and DMF (15 mL).Sodium hydride (60% by weight in oil, 229 mg, 5.73 mmol) was added inone portion. After stirring at room temperature for 10 minutes,iodomethane (1.02 g, 7.16 mmol) was added and the reaction stirred atroom temperature for 1.5 h. The reaction was then quenched with aqueoussaturated sodium bicarbonate (10 mL) and the resulting solution pouredinto water (150 mL). The mixture was then extracted with ethyl acetate(250 mL). The organic layer was dried over sodium sulfate. The dryingagent was then removed by filtration, and the filtrate was concentratedunder reduced pressure to residue. Purification by column chromatographyafforded 103e in a 68% yield (722 mg) as a white solid: mp 107-108° C.;¹H NMR (300 MHz, CDCl₃) δ 7.62 (s, 1H), 3.81 (s, 3H).

Example 103f6-Chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one103f

A 250-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with4-bromo-6-chloro-2-methylpyridazin-3(2H)-one 103e (1.90 g, 8.53 mmol),101e (1.18 g, 7.75 mmol) and 1,4-dioxane (40 mL). The flask was purgedwith nitrogen and cooled to 0° C. A 1 M solution of lithiumhexamethyldisilazide in THF (39 mL, 39.0 mmol) was added. After bubblingnitrogen through the resulting suspension for 30 min, Xantphos (381 mg,0.659 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (355 mg, 0.388mmol) were added, and the reaction mixture was heated at reflux for 2 h.After this time, the mixture was cooled to room temperature and dilutedwith water (10 mL). The pH of the solution was adjusted to 7.6 with 2 Nhydrochloric acid. The organic layer was separated, and the aqueouslayer was extracted with ethyl acetate (3×40 mL). The combined organiclayers were dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromato-graphy on silicato afford a 76% yield (1.74 g) of 103f as an off-white solid: mp184-186° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.62 (s, 1H), 7.72 (s, 1H),6.00 (s, 1H), 4.04 (t, 2H, J=5.1 Hz), 3.65 (s, 3H), 3.53 (s, 2H), 2.82(t, 2H, J=5.1 Hz), 2.37 (s, 3H); MS (ESI+) m/z 295.1 (M+H).

A 150-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with103d (580 mg, 1.43 mmol), 103f (300 mg, 1.00 mmol), sodium carbonate(320 mg, 3.00 mmol), 1,4-dioxane (8 mL), DMF (5 mL) and water (2.5 mL).This mixture was degassed with nitrogen for 30 min.Tetrakis(triphenylphosphine)palladium (120 mg, 0.103 mmol) was added.After heating at reflux for 14 h, the reaction mixture was cooled toroom temperature and partitioned between water (40 mL) and methylenechloride (100 mL). The layers were separated, and the aqueous phase wasextracted with methylene chloride (2×50 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by flashchromatography to afford 103 in 44% yield (240 mg) as an off-whitesolid: mp 175-176° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.20(m, 1H), 8.04 (s, 1H), 7.81 (s, 1H), 7.56 (m, 3H), 7.40 (m, 2H), 5.99(s, 1H), 5.12 (s, 1H), 3.97 (t, 2H, J=5.5 Hz), 3.76 (s, 3H), 3.51 (s,2H), 2.79 (t, 2H, J=8.5 Hz), 2.35 (s, 3H), 2.17 (s, 3H); MS (ESI+) m/z538.2 (M+H).

Example 1045-[2-(Hydroxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one104 Example 104aN-Methoxy-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide104a

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen, charged with4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (3.00 g, 16.5mmol), methylene chloride (80 mL), and DMF (60 mg, 0.825 mmol) andcooled to 0° C. To the resulting solution, oxalyl chloride (2.31 g, 18.2mmol) was added dropwise. After this addition was complete, the reactionwas warmed to room temperature and stirred for 2 h. After this time, thereaction was concentrated to dryness under reduced pressure. Theresulting white solid was dissolved in methylene chloride (80 mL) andthe solution cooled to 0° C. Triethylamine (5.00 g, 49.5 mmol) andN,O-dimethylhydroxylamine (1.61 g, 16.5 mmol) were then added. After theaddition was complete, the cooling bath was removed, and the reactionmixture was stirred at room temperature for 16 h. After this time, thereaction mixture was partitioned between water (100 mL) and ethylacetate (200 mL). The layers were separated, and the aqueous phase wasextracted with ethyl acetate (100 mL). The combined organic extractswere washed with water (100 mL), followed by brine (100 mL) and driedover sodium sulfate. The drying agent was removed by filtration, and thesolvent was evaporated under reduced pressure. The resulting residue waspurified by flash chromatography to afford an 88% yield of 104a (3.29 g)as a white solid: mp 36-37° C.; ¹H NMR (500 MHz, CDCl₃) d 7.79 (s, 1H),3.76 (s, 3H), 3.34 (s, 3H), 2.78 (t, 2H, J=6.0 Hz), 2.62 (t, 2H, J=6.0Hz), 1.82 (m, 4H); MS (APCI+) m/z 226.3 (M+H)

Example 104b3-Chloro-1-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)propan-1-one 104b

A 100-mL single-necked round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 104a (2.70 g, 12.0mmol) and anhydrous THF (45 mL), and the solution was cooled to −10° C.with acetone/ice bath. A 1.0 M solution of vinylmagnesium bromide in THF(13.2 mL, 13.2 mmol) was added dropwise, and the resulting reactionmixture was stirred at 0° C. for 4 h. After this time, the reactionmixture was partitioned between ethyl acetate (100 mL) and 2 M aqueoushydrochloric acid (40 mL). The layers were separated, and the aqueousphase was extracted with ethyl acetate (40 mL). The combined organicextracts were washed with water (100 mL), followed by brine (100 mL),dried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was dissolved in methylene chloride (30mL), and a 2 M solution of hydrogen chloride in diethyl ether (15 mL)was added. After stirring at room temperature for 1 h, the solvents wereremoved under reduced pressure. Purification of the resulting residue bycolumn chromatography afforded a 29% yield (804 mg) of 104b as anoff-white solid: mp 57-58° C.; ¹H NMR (500 MHz, CDCl₃) d 7.41 (s, 1H),3.89 (t, 2H, J=7.0 Hz), 3.30 (t, 2H, J=7.0 Hz), 2.81 (t, 2H, J=6.0 Hz),2.64 (t, 2H, J=6.0 Hz), 1.83 (m, 4H); MS (ECI+) m/z 229.1 (M+H)

Example 104c5,6,7,8-Tetrahydro-1H-benzo[b]cyclopenta[d]thiophen-3(2H)-one 104c

A 50-mL single-necked round-bottomed flask equipped with a magneticstirrer was charged with 104b (800 mg, 3.51 mmol) and 98% sulfuric acid(8 mL). After stirring at 95° C. for 16 h, the reaction mixture waspoured into ice (50 g), and the resulting suspension was extracted withethyl acetate (3×50 mL). The organic extracts were combined, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography to afford 104c in47% yield (320 mg) as an off-white solid: mp 75-76° C.; ¹H NMR (500 MHz,CDCl₃) d 2.89 (m, 2H), 2.87-2.83 (m, 4H), 2.56 (t, 2H, J=6.5 Hz), 1.84(m, 4H)

Example 104d5,6,7,8-Tetrahydro-1H-benzo[b]cyclopenta[d]thiophen-3(2H)-one oxime 104d

A 100-mL single-neck round-bottomed flask equipped with a mechanicalstirrer and nitrogen inlet was charged with hydroxylamine hydrochloride(573 mg, 8.25 mmol) and methanol (10 mL). The mixture was cooled to 0°C. using an ice bath. Sodium acetate (677 mg, 8.25 mmol) was added. Themixture was stirred at 0° C. for 30 min. After this time, 104c (319 mg,1.65 mmol) was added, and the reaction was stirred at room temperaturefor 16 h.

After this time, the mixture was concentrated, and the resulting residuewas triturated with water (10 mL). The resulting solid was collected anddried in a vacuum oven at 45° C. to afford an 84% yield (287 mg) of 104das an off-white solid: mp 173-174° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 10.38(s, 1H), 2.97 (m, 2H), 2.77-2.73 (m, 4H), 2.47 (m, 2H), 1.75 (m, 4H); MS(APCI+) m/z 208.3 (M+H).

Example 104e 3,4,5,6,7,8-Hexahydrobenzothieno[2,3-c]pyridin-1(2H)-one104e

A 50-mL single-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 104d(285 mg, 1.38 mmol) and polyphosphoric acid (15 g). After stirring at80° C. for 16 h, the reaction mixture was cooled to room temperature,and water (30 mL) was added. The resulting mixture was stirred for 30min and filtered. The filter cake was washed with water (20 mL) anddried in a vacuum oven at 45° C. to afford a 75% yield (215 mg) of 104eas an off-white solid: mp 203° C. dec; ¹H NMR (500 MHz, CDCl₃) d 5.62(s, 1H), 3.59 (t, 2H, J=7.0 Hz), 2.81 (t, 2H, J=6.0 Hz), 2.72 (t, 2H,J=7.0 Hz), 2.48 (t, 2H, J=6.0 Hz), 1.84 (m, 4H). MS (APCI+) m/z 208.3(M+H)

Example 104f2-Bromo-6-(1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzylacetate 104f

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 104e(214 mg, 1.04 mmol), 2,6-dibromobenzyl acetate 104g (519 mg, 2.08 mmol),cesium carbonate (678 mg, 2.08 mmol), N,N′-dimethylethylenediamine (92mg, 1.04 mmol) and 1,4-dioxane (10 mL). After bubbling nitrogen throughthe resulting suspension for 30 min, copper iodide (99 mg, 0.520 mmol)was added, and the reaction mixture was heated at 100° C. (oil bathtemperature) for 16 h. After this time, the mixture was cooled to roomtemperature and filtered. The filtrate was diluted with ethyl acetate(100 mL) and water (50 mL). The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatography toafford a 30% yield (138 mg) of2-Bromo-6-(1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzylacetate 104f as a yellow oil: ¹H NMR (500 MHz, CDCl₃) d 7.59 (dd, 1H,J=7.0, 1.5 Hz), 7.30-7.24 (m, 2H), 5.23 (m, 2H), 4.06 (m, 1H), 3.77 (m,1H), 2.98 (m, 1H), 2.83-2.77 (m, 3H), 2.50 (m, 2H), 2.04 (s, 3H), 1.85(m, 4H)

Example 104g 2,6-dibromobenzyl acetate 104g

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and nitrogen inlet was purged with nitrogenand charged with 2,6-dibromotoluene (2.50 g, 10.0 mmol),N-bromosuccinimide (1.78 g, 10.0 mmol) and carbon tetrachloride (40 mL).The solution was heated to 80° C. (oil bath temperature), and2,2′-azobisisobutyronitrile (164 mg, 1.00 mmol) was added. The resultingmixture was refluxed for 14 h. After that time, the mixture was cooledto room temperature and filtered. The filter cake was washed with carbontetrachloride (2×20 mL). The filtrate was diluted with ethyl acetate(200 mL) and washed with water (40 mL), saturated aqueous sodiumbicarbonate (40 mL) and brine (40 mL). The organic layer was dried oversodium sulfate and concentrated under reduced pressure to afford aquantative yield (3.28 g) of 1,3-dibromo-2-(bromomethyl)benzene as ayellow solid: mp 77-78° C.; ¹H NMR (300 MHz, CDCl₃) d 7.55 (d, 2H, J=8.1Hz), 7.07 (t, 1H, J=8.1 Hz), 4.83 (s, 2H)

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was purged with nitrogen and charged with1,3-dibromo-2-(bromomethyl)benzene (3.28 g, 10.0 mmol), potassiumacetate (3.93 g, 40.0 mmol) and DMF (100 mL). The solution was stirredat room temperature for 14 h. After that time, the reaction mixture wasdiluted with water (900 mL) and extracted with ethyl acetate (3×200 mL).The combined organic layers were washed with brine (100 mL), dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography to afford an 88% yield (2.70 g) of2,6-dibromobenzyl acetate 104g as an off-white solid: mp 62-65° C.; ¹HNMR (300 MHz, CDCl₃) d 7.57 (d, 2H, J=8.0 Hz), 7.07 (t, 1H, J=7.9 Hz),5.42 (s, 2H), 2.11 (s, 3H); MS (ESI+)

Example 104h1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one104h

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and thermoregulator was purged with nitrogen and charged with5-bromo-1-methyl-3-(pyrimidin-4-ylamino)pyridin-2(1H)-one 109b (300 mg,1.07 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(534 mg, 2.14 mmol), potassium acetate (210 mg, 2.14 mmol) and1,4-dioxane (10 mL). A stream of nitrogen was passed through theresulting suspension for 30 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complexwith dichloromethane (PddppfCl₂.CH₂Cl₂, 39 mg, 0.054 mmol) was thenadded, and the reaction was stirred at 95° C. for 30 min. After thistime, the mixture was cooled to ambient temperature, partitioned betweenwater (40 mL) and ethyl acetate (60 mL) and filtered through a plug ofCelite 521. The organic phase was separated, dried over sodium sulfate,filtered and concentrated under reduced pressure to afford crude 104h asa black oil which was used directly in the next step without furtherpurification. MS (ESI+) m/z 329.1 (M+H)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with104f (136 mg, 0.313 mmol), crude 104h (1.07 mmol, presumed quantitativeyield), sodium carbonate (100 mg, 0.940 mmol), 1,4-dioxane (5 mL) andwater (1 mL). This mixture was degassed with nitrogen for 30 min.Tetrakis(triphenyl-phosphine)palladium mixture (636 mg, 0.031 mmol) wasadded. After heating at 100° C. for 3 h, the reaction was cooled to roomtemperature and partitioned between water (40 mL) and methylene chloride(100 mL). The layers were separated, and the aqueous phase was extractedwith methylene chloride (2×50 mL). The organic extracts were combined,dried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was dissolved in methanol (5 mL), andpotassium carbonate (500 mg, 3.62 mmol) was added. After stirring atroom temperature for 2 h, the reaction mixture was partitioned betweenwater (20 mL) and methylene chloride (20 mL). The layers were separated,and the aqueous phase was extracted with methylene chloride (2×20 mL).The organic extracts were combined, dried over sodium sulfate, filteredand concentrated under reduced pressure. The resulting residue waspurified by flash chromatography to afford 104 in 26% yield (42 mg) as awhite solid: mp>250° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.71(d, 1H, J=2.5 Hz), 8.64 (s, 1H), 8.29 (d, 1H, J=6.0 Hz), 7.52 (d, 1H,J=2.5 Hz), 7.45 (t, 1H, J=7.5 Hz), 7.36-7.30 (m, 3H), 4.84 (t, 1H, J=3.5Hz), 4.36 (m, 2H), 4.03 (m, 1H), 3.87 (m, 1H), 3.60 (s, 3H), 2.96 (m,1H), 2.85 (m, 1H), 2.77 (m, 2H), 2.58-2.46 (m, 2H), 1.79 (m, 4H); MS(APCI+) m/z 514.2 (M+H)

Example 10510-[2-(Hydroxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one105 Example 105a 3,3-Dimethylcyclopentanone 105a

A 1-L three-neck round-bottomed flask equipped with a magnetic stirrer,addition funnel and nitrogen inlet was purged with nitrogen and chargedwith ether (200 mL) and copper (I) iodide (54.46 g, 0.286 mol). Themixture was cooled to 0° C., methyllithium (1.6 M in ether, 357.5 mL,0.572 mol) was added dropwise to the reaction mixture over 1.5 h andstirred at 0° C. for additional 2 h. After this time a solution of3-methylcyclo-pent-2-enone (25 g, 0.260 mol) in ether (150 mL) was addeddropwise over 1.5 h. The reaction mixture was then stirred at 0° C. for2 h and poured into sodium sulfate deca-hydrate (300 g). The resultingmixture was stirred for 30 min. After this time the mixture was filteredand washed with ether (1000 mL). The filtrate was concentrated anddistilled under reduced pressure to afford a 70% yield (20.5 g) of3,3-dimethylcyclo-pentanone 105a as a colorless liquid: by 50-55° C. (at10 mmHg); ¹H NMR (300 MHz, CDCl₃) d 2.31 (t, 2H, J=7.8 Hz), 2.05 (s,2H), 1.79 (t, 2H, J=7.8 Hz); MS (ESI+) m/z 113.3 (M+H)

Example 105b Ethyl5,5-Dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylate 105b

A 500-mL three-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser, addition funnel and nitrogen inlet was purgedwith nitrogen and charged with DMF (9.49 g, 0.100 mol) and methylenechloride (100 mL). The reaction mixture was cooled to 0° C. andphosphorus oxychloride (14.1 g, 0.920 mol) was added dropwise to thereaction over 30 min. Once this addition was complete, the reaction waswarmed to room temperature and stirred for 1 h. After this time asolution of 105a (11.2 g, 0.100 mol) in methylene chloride (100 mL) wasadded dropwise over 1 h. The reaction was then stirred at reflux for 18h. The reaction mixture was cooled to room temperature and poured into amixture of crushed ice (400 mL) and sodium acetate (100 g, 1.22 mol).The resulting mixture was stirred for 45 min. After this time theaqueous layer was separated and extracted with methylene chloride (2×500mL). The combined organic layers were then washed with water (2×200 mL),followed by brine (200 mL) and dried over sodium sulfate. The dryingagent was then removed by filtration, and the filtrate was concentratedto afford crude product 2-chloro-4,4-dimethylcyclopent-1-enecarbaldehydewhich was placed in a 500-mL three-neck round bottomed flask equippedwith a mechanical stirrer, reflux condenser and nitrogen inlet.Methylene chloride (200 mL), ethyl 2-mercaptoacetate (11.0 g, 0.092 mol)and triethylamine (30 g, 0.207 mol) were then added. The reactionmixture was then stirred at reflux for 6 h. After this time the reactionwas cooled to room temperature and concentrated to a thick orangeresidue. Ethanol (200 mL) and triethylamine (30.0 g, 0.207 mol) wereadded and the reaction was heated at reflux for 12 h. The reaction wasthen cooled to room temperature and concentrated under reduced pressureand the resulting residue was diluted with ether (600 mL). The resultingmixture was washed with 1 M hydrochloric acid (150 mL), brine (100 mL),dried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography toafford 105b in 34% yield (7.70 g) as a colorless liquid: ¹H NMR (300MHz, CDCl₃) d 7.48 (s, 1H), 4.33 (q, 2H, J=7.2 Hz), 2.72 (s, 2H), 2.56(s, 2H), 1.38 (t, 3H, J=1.8 Hz), 1.17 (s, 6H); MS (ESI+) m/z 225.1

Example 105c5,5-Dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylic acid105c

In a 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser, 105b (4.00 g, 17.8 mmol) was dissolved inethanol (50 mL). THF (50 mL), water (50 mL) and lithium hydroxide (854mg, 35.6 mmol) were added, and the mixture was stirred at 60° C. for 4h. After this time the reaction was cooled to room temperature andacidified with 2M hydrochloric acid to pH 1.5, and then extracted withethyl acetate (2×200 mL). The organic layers were combined, washed withwater (2×100 mL), followed by brine (100 ml) and dried over sodiumsulfate. The drying agent was then separated by filtration. Afterevaporating the resulting filtrate, 105c was obtained in 91% yield (3.2g) as a white solid: mp 170-172° C.; ¹H NMR (300 MHz, CDCl₃) d 12.77 (s,1H), 7.46 (s, 1H), 2.71 (s, 2H), 2.53 (s, 2H), 1.20 (s, 6H); MS (ESI−)m/z 195.0

Example 105d5,5-Dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylic acid105d

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and a bubbler placed on the condenser wascharged with 105c (2.30 g, 11.6 mmol), toluene (25 mL), thionyl chloride(4.09 g, 34.9 mmol) and DMF (1 drop). The mixture was heated at refluxfor 1 h and then evaporated under reduced pressure on a rotaryevaporator at 45° C. The resulting acid chloride was diluted withmethylene chloride (20 mL).

In a separate 250-mL three-neck round-bottomed flask equipped with amagnetic stirrer N,O-dimethylhydroxylamine hydrochloride (2.26 g, 23.2mmol) and N,N-diisopropylethylamine (2.97 g, 23.0 mmol) were dissolvedin anhydrous methylene chloride (20 mL) under nitrogen, and the solutionwas cooled to 0° C. in an ice/water bath. The solution of the acidchloride was added, and the reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was extracted with water (100mL), 10% aqueous citric acid (50 mL) and a 1:1 mixture of saturatedaqueous sodium bicarbonate and water (100 mL). The organic layer wasdried over sodium sulfate and evaporated under reduced pressure on arotary evaporator to afford a 93% yield (2.60 g) of 105d as a lightyellow solid: ¹H NMR (300 MHz, CDCl₃) d 7.66 (s, 1H), 3.77 (s, 3H), 3.35(s, 3H), 2.74 (s, 2H), 2.58 (s, 2H), 1.23 (s, 6H)

Example 105e3-Chloro-1-(5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)propan-1-one105e

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 105d (2.41 g, 10.0mmol) and anhydrous THF (20 mL). The solution was cooled to −70° C., and1 M vinylmagnesium bromide in THF (11 mL, 11.0 mmol) was added with thereaction temperature maintained below −60° C. The reaction mixture wasstirred at −13 to −7° C. for 2 h and then warmed to room temperatureover 30 min. The reaction was again cooled to −70° C., and a 2 Msolution of hydrogen chloride in ether (22.5 ml, 45 mmol) was added. Thereaction was then stored in a freezer at −10° C. overnight. After thistime the mixture was evaporated under reduced pressure on a rotaryevaporator, and the resulting residue partitioned between water (100 mL)and ether (100 mL). The ether extract was dried over sodium sulfate andevaporated under reduced pressure on a rotary evaporator to afford crude105e (2.86 g, 118%) as a brown oil with approximately 75% purity (byNMR): ¹H NMR (300 MHz, CDCl₃) d 7.45 (s, 1H), 3.89 (t, 2H, J=6.9 Hz),3.30 (t, 2H, J=6.9 Hz), 2.75 (s, 2H), 2.59 (s, 2H), 1.24 (s, 6H)

Example 105f 6,6-Dimethyl-1,2,6,7-tetrahydrodicyclopenta[b,d]thiophen-3(5H)-one 105f

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with crude 105e (2.86 g, 10.0 mmol presumingquantitative yield) and 98% sulfuric acid. The reaction mixture washeated in a 90° C. oil bath overnight. The reaction mixture was placedinto an ice/acetone bath, and a cold (5° C.) solution of dipotassiumhydrogen phosphate (105 g, 0.603 mol) in water (300 mL) was added in oneportion. The resulting mixture was shaken with ethyl acetate (300 mL)and filtered. The filter cake was washed with ethyl acetate (100 mL).The ethyl acetate layer of the filtrate was separated, dried over sodiumsulfate and evaporated under reduced pressure on a rotary evaporator.the resulting residue was purified by flash column chromatography(silica, 80:20 hexanes/ethyl acetate) to afford 105f in 37% yield overtwo steps (683 mg) as an amorphous brown solid: mp 60-62° C.; ¹H NMR(500 MHz, CDCl₃) d 2.92-2.87 (m, 4H), 2.79 (s, 2H), 2.53 (s, 2H), 1.26(s, 6H); MS (ESI+) m/z 207.0 (M+H)

Example 105g6,6-Dimethyl-1,2,6,7-tetrahydrodicyclopenta[b,d]thiophen-3(5H)-one 105g

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with hydroxylamine hydrochloride(688 mg, 9.90 mmol), sodium acetate (812 mg, 9.90 mmol) and methanol (10mL), and the mixture at room temperature for 30 min. After this time, asolution of 105f (680 mg, 3.30 mmol) was added dropwise at roomtemperature, and the reaction was stirred at room temperature for 14 hunder nitrogen atmosphere. Since the reaction was not complete,hydroxylamine hydrochloride (1.15 g, 16.5 mmol) and sodium acetate (1.35g, 16.5 mmol) were added, and the stirring was continued at roomtemperature for 58 h. After this time, the mixture was diluted withmethylene chloride (150 mL) and water (100 mL), and the layers wereseparated. The organic layer was washed with brine (50 mL) and driedover sodium sulfate. The drying agent was removed by filtration and thefiltrate was concentrated to afford crude 105g in quantitative yield(730 mg) as a yellow semi-solid which was used in the next step withoutpurification: mp 122-124° C.; ¹H NMR for major isomer (500 MHz, CDCl₃) d3.13-3.11 (m, 2H), 2.85-2.83 (m, 2H), 2.77 (s, 2H), 2.49 (s, 2H), 1.24(s, 6H); MS (ESI+) m/z 222.0 (M+H).

Example 105h6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-one105h

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, mechanical stirrer and nitrogen inlet was charged with 105g(700 mg, 3.16 mmol) and polyphosphoric acid (25 g). The reaction mixturewas stirred at 80° C. for 13 h under nitrogen atmosphere. After thistime, the mixture was cooled to 0° C. and water (50 mL) was addeddropwise carefully maintaining the internal temperature between 10-45°C. The mixture was diluted with 90:10 methylene chloride/methanol (100mL) and the layers were separated. The aqueous layer was extracted with90:10 methylene chloride/methanol (50 mL), and the combined organiclayers were washed with saturated aqueous sodium bicarbonate (50 mL),brine (150 mL) and dried over sodium sulfate. The drying agent wasremoved by filtration. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by flash columnchromatography (silica, 95:5 methylene chloride/methanol) to afford6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-one105h in 90% yield (630 mg) as an amorphous off-white solid: mp 205-207°C.; ¹H NMR (500 MHz, CDCl₃) d 5.51 (s, 1H), 3.60-3.56 (m, 2H), 2.76-2.73(m, 4H), 2.49 (s, 2H), 1.26 (s, 6H); MS (ESI+) m/z 222.0 (M+H)

Example 105i(2-Bromo-6-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}phenyl)methylAcetate 105i

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 105h (624 mg, 2.82 mmol),2,6-dibromobenzyl acetate 104g (1.73 g, 5.65 mmol), cesium carbonate(1.84 g, 5.65 mmol), N,N′-dimethylethylenediamine (249 mg, 2.82 mmol)and 1,4-dioxane (15 mL). After bubbling nitrogen through the resultingsuspension for 30 min, copper iodide (269 mg, 1.41 mmol) was added. Areflux condenser was attached to the flask, and the reaction mixture washeated at 90° C. for 14 h. After this time, the mixture was cooled toroom temperature and filtered. The filtrate was diluted with ethylacetate (100 mL) and water (50 mL), and the layers were separated. Theaqueous layer was extracted with ethyl acetate (2×30 mL), and thecombined organic layers were washed with brine (100 mL) and dried oversodium sulfate. The drying agent was removed by filtration. The filtratewas concentrated under reduced pressure, and the resulting residue waspurified by flash column chromatography (silica, 70:30 hexanes/ethylacetate) to afford 105i in 52% yield (660 mg) as a white solid: mp126-128° C.; ¹H NMR (500 MHz, CDCl₃) d 7.60 (dd, J=7.5, 1.5 Hz, 1H),7.29-7.24 (m, 2H), 5.24 (s, 2H), 4.05-3.99 (m, 1H), 3.78-3.74 (m, 1H),3.06-2.99 (m, 1H), 2.84-2.80 (m, 1H), 2.77 (s, 2H), 2.52 (s, 2H), 2.05(s, 3H), 1.27 (s, 6H); MS (ESI+) m/z 448.0 (M+H)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 105i (250 mg, 0.558 mmol),crude1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one104h prepared above, 400 mg, 0.951 mmol, presuming quantitative yield inthe previous step), sodium carbonate (177 mg, 1.67 mmol), DMF (2 mL),water (2 mL) and 1,4-dioxane (10 mL). After bubbling nitrogen throughthe resulting suspension for 30 min,tetrakis(triphenylphosphine)palladium(0) (129 mg, 0.112 mmol) was added.A reflux condenser was attached to the flask, and the reaction mixturewas heated at 100° C. for 12 h. After this time, the mixture was dilutedwith 90:10 methylene chloride/methanol (100 mL) and water (75 mL), andthe layers were separated. The aqueous layer was extracted with 90:10methylene chloride/methanol (2×50 mL), and the combined organic layerswere washed with brine (100 mL) and dried over sodium sulfate. Thedrying agent was removed by filtration. The filtrate was concentratedunder reduced pressure, and the resulting residue was dissolved in THF(5 mL), water (5 mL) and methanol (5 mL). Lithium hydroxide monohydrate(117 mg, 2.79 mmol) was added, and the mixture was stirred at roomtemperature for 2 h. After this time, the mixture was diluted with 90:10methylene chloride/methanol (100 mL) and water (50 mL), and the layerswere separated. The aqueous layer was extracted with 90:10 methylenechloride/methanol (2×75 mL), and the combined organic layers were washedwith brine (100 mL) and dried over sodium sulfate. The drying agent wasremoved by filtration. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by flash columnchromatography (silica, 90:10 methylene chloride/methanol) andpreparative HPLC (70:30 water/acetonitrile) to afford 105 in 14% yield(42 mg) as an amorphous off-white solid: mp 252-254° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.71 (s, 1H), 8.64 (s, 1H), 8.30 (d, J=6.0Hz, 1H), 7.53 (s, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.37-7.31 (m, 3H),4.86-4.85 (m, 1H), 4.40-4.32 (m, 2H), 4.05-4.00 (m, 1H), 3.88-3.84 (m,1H), 3.60 (s, 3H), 3.05-2.99 (m, 1H), 2.91-2.88 (m, 1H), 2.75 (s, 2H),2.57-2.53 (m, 2H), 1.23 (s, 6H); MS (ESI+) m/z 528.2 (M+H)

Example 1062-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one106

Example 106 was prepared using the same procedure as example 136e andExample 136 except using 113a and 136d to yield 20 mg of 106 as a whitesolid. MS (ESI+) m/z 525 (M+H).

Example 1072-(2-(hydroxymethyl)-3-(1-methyl-5-(5-morpholinopyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one107

Example 107 was prepared using the same procedure as example 301 using255c and 114a as starting material to yield 122 mg of 107 as a whitesolid. MS (ESI+) m/z 581 (M+H).

Example 1082-(3-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one108 Example 108a 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 108a

A sealed tube equipped with a magnetic stirrer was charged with1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 101c (4 g, 12.9mmol) 0.5M ammonia solution in dioxane (200 mL). The resulting mixturewas carefully heated to 50° C. overnight. After this time, the reactionmixture was concentrated under reduced pressure, and to the residue wasadded H₂O (50 mL) and EtOAc (50 mL). The aqueous layer was separated andextracted with EtOAc (2×50 mL). The combined organic extracts werewashed with brine (100 mL) and dried over sodium sulfate. The resultingsolution was concentrated under reduced pressure to afford a 100% yield(2.1 g) of crude 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 108a.

Example 108b1-(2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone 108b

A 200 mL round bottom flask was charged with2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 108a (2.1 g, 12.9mmol), triethylamine (5.5 mL, 38.7 mmol), acetyl chloride (1.1 mL, 15.5mmol) and CH₂Cl₂ (100 mL). The mixture stirred at room temperature overnight. After this time, the reaction mixture was concentrated underreduced pressure, and to the residue was added H₂O (50 mL) and EtOAc (50mL). The aqueous layer was separated and extracted with EtOAc (2×50 mL).The combined organic extracts were washed with brine (100 mL). Thecombined aqueous extracts were back extracted with 9:1 CH₂Cl₂:MeOH (2×50mL). The combined organics were dried over sodium sulfate. The resultingresidue was purified by column chromatography eluting with a gradient ofCH₂Cl₂—9:1 CH₂Cl₂:MeOH to afford a 84% yield (2.3 g) of1-(2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone 108b.

Example 108c1-(2-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone 108c

A 500-mL Parr hydrogenation bottle was charged with1-(2-nitro-6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone 108b(2.3 g, 10.9 mmol), 10% palladium on carbon (50% wet, 570 mg dry weight)and ethanol (100 mL). The bottle was evacuated, charged with hydrogengas to a pressure of 50 psi and shaken for 2 h on a Parr hydrogenationapparatus. The catalyst was removed by filtration through a pad ofCelite 521 washing with 1:1 CH₂Cl₂:MeOH (500 mL). The resulting solutionwas concentrated under reduced pressure to afford a 95% yield (1.9 g) ofcrude 1-(2-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone108c.

Example 108d3-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one108d

A sealed tube was equipped with a magnetic stirrer and charged with1-(2-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone 108c (860mg, 4.8 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.8 g, 6.7 mmol),and cesium carbonate (3.4 g, 10.5 mmol) in 1,4-dioxane (67 mL). Afterbubbling nitrogen through the solution for 30 min, Xantphos (330 mg, 0.6mmol) and tris(dibenzylideneacetone)dipalladium(0) (300 mg, 0.3 mmol)were added, and the reaction mixture was heated to 100° C. for 16 h.After this time, H₂O (50 mL) and EtOAc (50 mL) were added. The aqueouslayer was separated and extracted with EtOAc (2×50 mL). The combinedorganic extracts were washed with brine (100 mL) and dried over sodiumsulfate. The resulting residue was purified by column chromatographyeluting with a gradient of CH₂Cl₂—60:35:5 CH₂Cl₂:Et₂O:MeOH to afford a41% yield (720 mg) of3-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one108d.

Example 108e2-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 108e

A microwave tube equipped with a magnetic stirrer was charged with3-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one108d (120 mg, 0.3 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (200 mg, 0.4 mmol), DME (4 mL) and 1M aqueous sodiumcarbonate (1 mL). After bubbling nitrogen for 15 min, Pd(PPh₃)₄ (19 mg,0.02 mmol) was added. The mixture was heated in a microwave to 130° C.for 15 min. After this time, ethyl acetate (5 mL) and water (5 mL) wereadded. The separated aqueous layer was extracted with EtOAc (2×5 mL).The combined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography eluting with a gradient ofCH₂Cl₂—60:35:5 CH₂Cl₂:Et₂O:MeOH to afford a 33% yield (69 mg) of2-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 108e.

A 25 mL round bottom flask with a magnetic stirrer was charged with2-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 108e (69 mg, 0.11 mmol), lithium hydroxide (8 mg, 0.3 mmol), THF(1 mL), i-PrOH (1 mL) and water (2 mL). The mixture stirred at rt for 2h. After this time, EtOAc (3 mL) and water (3 mL) were added. Theseparated aqueous layer was extracted with EtOAc (2×5 mL). The combinedorganics were washed with brine (10 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography eluting with a gradient ofCH₂Cl₂—75:18:7 CH₂Cl₂:Et₂O:MeOH to afford a 63% yield (40 mg) of2-(3-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one108. MS (ESI+) m/z 582.3 (M+H).

Example 1092-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one109 Example 109a2-bromo-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 109a

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 101k (720 mg, 3.78mmol), 2,6-dibromobenzyl acetate 104g (2.33 g, 7.57 mmol), cesiumcarbonate (2.47 g, 7.57 mmol), N,N′-dimethylethylenediamine (333 mg,3.78 mmol) and 1,4-dioxane (31 mL). After bubbling nitrogen through theresulting suspension for 30 min, copper iodide (360 mg, 1.89 mmol) wasadded, and the reaction mixture was heated at 105° C. (oil bathtemperature) for 3 days. After this time, the mixture was cooled to roomtemperature and filtered. The filtrate was diluted with ethyl acetate(200 mL) and water (40 mL). The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatography toafford a 31% yield (490 mg) of2-bromo-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 109a.

Example 109b 5-bromo-1-methyl-3-(pyrimidin-4-ylamino)pyridin-2(1H)-one109b

A solution of pyrimidin-4-amine (2.0 g, 21 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (6.2 g, 23.1 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.96 g, 1.1 mmol), Xantphos(1.03 g, 1.79 mmol), and cesium carbonate (7.5 g, 23 mmol) in dioxane(25 mL) was heated in a sealed tube at 130° C. for 18 hours. The mixturewas diluted with CH₂Cl₂ (100 mL) and filtered through a plug of celite.The solution was concentrated in vacuo on the rotary evaporator. Thematerial was then dissolved in minimal CH₂Cl₂ (5 mL) and was trituratedwith Et₂O (80 mL). The product was then filtered and washed with Et₂O(100 mL) to afford 2.9 g (49%) of 109b.

Example 109c1-Methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one109c

A solution of 5-bromo-1-methyl-3-(pyrimidin-4-ylamino)pyridin-2(1H)-one109b (600 mg, 2.13 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (596 mg,2.35 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (174 mg, 0.213 mmol), potassium acetate(628 mg, 6.40 mmol) in dioxane (4.5 mL) was sealed in a microwave tubeand heated to 130° C. for 10 minutes. The solution was filtered througha plug of celite and concentrated. The crude1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one109c was carried on to the next step without purification.

A solution of 109c (crude, 2.13 mmol), 109a (300 mg, 0.719 mmol),tetrakis(triphenylphosphine)palladium(0) (83 mg, 0.0719 mmol), andsodium carbonate (229 mg, 2.16 mmol) in dioxane (4.5 mL) and water (2.3mL) was sealed in a microwave tube and heated to 130° C. for 10 minutes.The organics layer was separated from the aqueous and filtered through aplug of celite. The material was then adsorbed to celite and waspurified via silica chromatography using 0-100% ethyl acetate in hexanesfollowed by a switch to 0-15% methanol in dichloromethane to afford 105mg (27%) of 109.

Example 1102-(3-(5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one110 Example 110a 2-Nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine 110a

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 101c (3.00 g, 9.59 mmol)and 4M aqueous hydrobromic acid (120 mL), and the resulting mixture washeated at reflux for 24 h. After this time, the reaction mixture wasconcentrated under reduced pressure to approximately 6 mL volume, andthe residue was stirred in 2M aqueous sodium hydroxide (40 mL) for 2 h.After this time methylene chloride was added (40 mL) and the mixture wasstirred for 15 min. The aqueous layer was separated and extracted withmethylene chloride (2×50 mL). The combined organic extracts were washedwith brine (100 mL) and dried over sodium sulfate. The drying agent wasremoved by filtration and the filtrate concentrated under reducedpressure to afford a 62% yield (1.01 g) of 110a as a white solid: mp110-112° C.; ¹H NMR (300 MHz, CDCl₃) 6.68 (s, 1H), 4.87 (s, 2H), 4.28(t, 2H, J=5.4 Hz), 4.20 (t, 2H, J=5.1 Hz); MS (ESI+) m/z 170.0 (M+H).

Example 110b 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine 110b

A 500-mL Parr hydrogenation bottle was purged with nitrogen and chargedwith 110a (1.01 g, 5.92 mmol), 10% palladium on carbon (50% wet, 125 mgdry weight) and ethanol (50 mL). The bottle was evacuated, charged withhydrogen gas to a pressure of 25 psi and shaken for 2 h on a Parrhydrogenation apparatus. The hydrogen was then evacuated and nitrogencharged to the bottle. The catalyst was removed by filtration through apad of Celite 521 and the filtrate concentrated under reduced pressure.The resulting residue was purified by column chromatography using 400 ccof silica gel and eluting with 3% methanol in methylene chloride. Thefractions containing 110b were collected to afford, after concentratingunder reduced pressure, a 73% yield (601 mg) of 110b as a yellow solid:mp 74-76° C. ¹H NMR (300 MHz, CDCl₃) d 5.37 (s, 1H), 4.72 (s, 2H), 4.07(t, 2H, J=5.1 Hz), 3.98 (t, 2H, J=5.1 Hz), 3.57 (br s, 2H); MS (ESI+)m/z 140.4 (M+H).

Example 110c5-Bromo-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methylpyridin-2(1H)-one110c

A 50-mL three-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and nitrogen inlet was charged with1,4-dioxane (20 mL), 110b (600 mg, 4.31 mmol), 3,5-dibromo-1-methylpyridine-2(1H)-one (1.44 g, 5.40 mmol) and cesium carbonate (3.08 g,9.48 mmol). After bubbling nitrogen through the resulting solution for30 min, Xantphos (300 mg, 0.52 mmol) andtris(dibenzylideneacetone)-dipalladium(0) (320 mg, 0.35 mmol) wereadded, and the reaction mixture was heated at reflux for 2 h. After thistime the reaction was cooled to room temperature, partitioned betweenethyl acetate (75 mL) and water (75 mL) and filtered. The aqueous layerwas separated and extracted with ethyl acetate (2×25 mL). The organiclayers were combined and washed with brine (50 mL) and dried over sodiumsulfate. The drying agent was removed by filtration and the filtrateconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography using 500 cc of silica gel and eluting with 1%methanol in methylene chloride. The fractions containing 110c werecollected to afford, after concentrating under reduced pressure, a 31%yield (433 mg) of 110c as a green solid: mp 195-197° C.; ¹H NMR (300MHz, CDCl₃) 7.92 (d, 1H, J=2.4 Hz), 7.44 (s, 1H), 6.90 (d, 1H, J=2.4Hz), 5.65 (s, 1H), 4.80 (s, 2H), 4.13 (s, 2H), 3.61 (s, 5H); MS (ESI+)m/z 324.9 (M+H).

Example 110d2-(5-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 110d

A microwave tube equipped with a magnetic stirrer was charged with5-bromo-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methylpyridin-2(1H)-one110c (130 mg, 0.4 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (220 mg, 0.5 mmol), DME (4 mL) and 1M aqueous sodiumcarbonate (1.2 mL). After bubbling N2 for 15 min, Pd(PPh₃)₄ (23 mg, 0.02mmol) was added. The mixture was heated in microwave to 130° C. for 20min. After this time, EtOAc (5 mL) and water (5 mL) were added. Theseparated aqueous layer was extracted with EtOAc (2×5 mL). The combinedorganics were washed with brine (10 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography eluting with a gradient ofCH₂Cl₂—60:35:5 CH₂Cl₂:Et₂O:MeOH to afford a 89% yield (210 mg) of 110d.

A 25 mL round bottom flask with a magnetic stirrer was charged with 110d(210 mg, 0.4 mmol), lithium hydroxide (45 mg, 1.1 mmol), THF (3.6 mL),i-PrOH (3.6 mL) and water (7.2 mL). The mixture stirred at rt for 3 h.After this time, EtOAc (10 mL) and water (10 mL) were added. Theseparated aqueous layer was extracted with EtOAc (2×10 mL). The combinedorganics were washed with brine (20 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography eluting with a gradient ofCH₂Cl₂—60:35:5 CH₂Cl₂:Et₂O:MeOH to afford a 57% yield (110 mg) of 110.MS (ESI+) m/z 541.3 (M+H).

Example 1115-[2-(Hydroxymethyl)-3-[4-methyl-5-oxo-6-(pyridine-3-ylamino)-4,5-dihydropyrazin-2-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-6-one111 Example 111a2-(1-Oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylAcetate 111a

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with104f (1.18 g, 2.72 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (2.04 g, 8.16mmol), potassium acetate (800 mg, 8.16 mmol) and 1,4-dioxane (20 mL). Astream of nitrogen was passed through the resulting suspension for 30min. [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (398mg, 0.544 mmol) was then added, and the reaction was stirred at 90° C.for 8 h. After this time, the mixture was cooled to ambient temperature,partitioned between water (25 mL) and ethyl acetate (50 mL) and filteredthrough a plug of Celite 521. The organic phase was separated, driedover sodium sulfate, filtered and concentrated under reduced pressure.the resulting residue was purified by flash chromatography to afford a77% yield (1.01 g) of 111a as a brown solid: ¹H NMR (500 MHz, CDCl₃) d7.81 (d, 1H, J=7.0 Hz), 7.41 (t, 1H, J=7.0 Hz), 7.37 (d, 1H, J=7.0 Hz),5.49 (d, 1H, J=11.5 Hz), 5.23 (d, 1H, J=11.5 Hz), 4.01 (m, 1H), 3.76 (m,1H), 2.96 (m, 1H), 2.81-2.75 (m, 3H), 2.50 (m, 2H), 1.99 (s, 3H), 1.86(m, 4H), 1.33 (s, 12H); MS (ESI+) m/z 482.2 (M+H).

Example 111b 5-Bromo-1-methyl-3-(pyridin-3-ylamino)pyrazin-2(1H)-one111b

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and nitrogen inlet was charged with THF (15mL), 3,5-dibromo-1-methyl pyrazin-2(1H)-one (1.00 g, 3.73 mmol),3-aminopyridine (351 mg, 3.73 mmol) and sodium tert-butoxide (789 mg,8.21 mmol). After bubbling nitrogen through the resulting solution for30 min, di-μ-bromobis(tri-t-butylphosphino)dipalladium(I) (29 mg, 0.037mmol) was added, and the reaction mixture was stirred at roomtemperature for 2.5 h. After this time the reaction was partitionedbetween ethyl acetate (50 mL) and water (50 mL) and filtered. Theaqueous layer was separated and extracted with ethyl acetate (2×25 mL).The organic layers were combined, washed with brine (50 mL) and driedover sodium sulfate. The drying agent was removed by filtration and thefiltrate concentrated under reduced pressure. The resulting residue waspurified by column chromatography to afford a 35% yield (370 mg) of 111bas a brown solid: mp>250° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.75 (s, 1H),9.08 (d, 1H, J=2.5 Hz), 8.32 (m, 1H), 8.24 (dd, 1H, J=5.0, 1.5 Hz), 7.40(s, 1H), 7.36 (dd, 1H, J=8.5, 4.5 Hz), 3.45 (s, 3H); MS (APCI+) m/z281.0 (M+H).

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with111a (134 mg, 0.279 mmol), 111b (71 mg, 0.253 mmol), sodium carbonate(80 mg, 0.759 mmol), 1,4-dioxane (5 mL) and water (1 mL). This mixturewas degassed with nitrogen for 30 min.Tetrakis(triphenyl-phosphine)palladium (29 mg, 0.025 mmol) was added.After heating at 100° C. for 3 h, the reaction mixture was cooled toroom temperature and partitioned between water (40 mL) and methylenechloride (100 mL). The layers were separated, and the aqueous phase wasextracted with methylene chloride (2×50 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was dissolved in methanol (5mL), and potassium carbonate (500 mg, 3.62 mmol) was added. Afterstirring at room temperature for 2 h, the reaction mixture waspartitioned between water (20 mL) and methylene chloride (20 mL). Thelayers were separated, and the aqueous phase was extracted withmethylene chloride (2×20 mL). The organic extracts were combined, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by flash chromatography to afford 111in 38% yield (49 mg) as a white solid: mp 164-165° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 9.54 (s, 1H), 9.14 (d, 1H, J=2.5 Hz), 8.42 (m, 1H), 8.18 (dd,1H, J=4.5, 1.5 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.49-7.46 (m, 2H), 7.34 (d,1H, J=8.0 Hz), 7.30 (dd, 1H, J=8.0, 4.5 Hz), 4.81 (m, 1H), 4.49 (dd, 1H,J=11.0, 3.5 Hz), 4.43 (dd, 1H, J=11.0, 6.5 Hz), 4.02 (m, 1H), 3.86 (m,1H), 3.56 (s, 3H), 2.95 (m, 1H), 2.86 (m, 1H), 2.77 (m, 2H), 2.58-2.46(m, 2H), 1.79 (m, 4H); MS (APCI+) m/z 514.2 (M+H).

Example 1122-(2-(hydroxymethyl)-3-(1-methyl-5-(5-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one112 Example 112a5-Bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 112a

A 250 ml sealed tube with a magnetic stirrer was charged with5-methyl-1H-pyrazol-3-amine (0.91 g, 9.36 mmol),3,5-dibromo-1-methyl-1H-pyridin-2-one (2.1 g, 7.87 mmol), cesiumcarbonate (7.6 g, 23.56 mmol) and 1,4-dioxane (78 mL). After degassingfor 10 minutes, tris(dibenzylideneacetone)dipalladium(0) (0.72 g, 0.8mmol) and Xantphos (0.91 g, 1.57 mmol) were added. The reaction mixturewas heated at 115° C. for 48 hours. Then the mixture was cooled to roomtemperature and partitioned between dichloro-methane (50 mL) and water(30 mL). The organic phase was separated, and the aqueous layer wasextracted with dichloromethane (3×30 mL). The combined organic phaseswere dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by flash column chromatography (silica, 9:1methylene chloride/methanol) to give 85% yield (1.88 g) of 112a as asolid: MS (ESI+) m/z 285.0 (M+H).

A 10 mL microwave vial with a magnetic stirrer was charged with2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (181 mg, 0.39 mmol), 112a (85 mg, 0.3 mmol), 1M sodiumcarbonate solution (1.2 mL, 1.2 mmol) and 1,2-dimethoxyethane (3 mL).After bubbling nitrogen through the resulting suspension for 10 min,tetrakis(triphenylphosphine)-palladium(0) (18 mg, 0.015 mmol) was added.The reaction mixture was heated at 130° C. for 10 minutes in a microwavereactor. Then ethyl acetate (10 mL) and water (5 mL) were added, and thelayers were separated. The aqueous layer was extracted with ethylacetate (2×10 mL), and the combined organic layers were washed withbrine and dried over sodium sulfate. The drying agent was removed byfiltration. The filtrate was concentrated under reduced pressure, andthe resulting residue was purified by flash column chromatography(silica, 60:35:5 methylene chloride/diethyl ether/methanol) to give 100mg mixture of 112b and 112 as a yellow residue. The residue wasdissolved in a mixture of THF (1 mL), water (0.5 mL) and isopropanol (1mL). Lithium hydroxide monohydrate (31 mg, 0.74 mmol) was added, and themixture was stirred at room temperature for 2 h. After this time, themixture was diluted with 90:10 methylene chloride/methanol (10 mL) andwater (5 mL), and the layers were separated. The aqueous layer wasextracted with 90:10 methylene chloride/methanol (2×10 mL), and thecombined organic layers were washed with brine and dried over sodiumsulfate. The drying agent was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by flash column chromatography (silica, 60:35:5 methylenechloride/ether/methanol) to afford a 18% yield (two steps, 28 mg) of2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one112 as a white solid: MS (ESI+) m/z 499.3 (M+H).

Example 1132-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridine-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one113 Example 113a Acetic Acid2-Bromo-6-(1-oxo-3,4,6,7,8,9-hexahydro-1H-pyrazino[1,2-a]indol-2-yl)-benzylEster 113a

A 350-mL sealed tube equipped with a magnetic stirring bar was chargedwith 3,4,6,7,8,9-hexahydro-2H-pyrazino[1,2-a]indol-1-one 101k (5.0 g,0.026 mol), 2,6-dibromobenzyl acetate 104g (16.2 g, 0.052 mol)N,N′-dimethylethylenediamine (2.6 mL, 0.026 mol), Cs₂CO₃ (17.0 g, 0.052mol), and 1,4-dioxane (80 mL). After a stream of nitrogen was passedthrough the resulting suspension for 30 min., CuI (2.5 g, 0.013 mol) wasadded and the resulting reaction mixture was stirred at 95° C. for 16 h.Then the mixture was cooled to room temperature, partitioned betweenEtOAc (50 mL) and water (50 mL), and the organic phase was extractedwith EtOAc (30 mL×3). The combined organic phases were washed with water(20 mL×2) and brine (20 mL×1), dried (Na₂SO₄), and concentrated. Thecrude product was purified by flash chromatography(dichloromethane:MeOH, 97:3) to give 35% yield (4.5 g) of 113a as whitesolids.

Example 113b Acetic Acid2-{1-Methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-6-(1-oxo-3,4,6,7,8,9-hexahydro-1H-pyrazino[1,2-a]indol-2-yl)-benzylEster 113b

In a 10-mL glass vessel equipped with a magnetic stirring bar wereplaced1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-1H-pyridin-2-one197f (210 mg, 0.49 mmol), 113a (250 mg, 0.60 mmol), Pd(PPh₃)₄ (50 mg,0.043 mmol) in 2 N Na₂CO₃ (2 mL) and 1,2-dimethoxyethane (5 mL). Thevessel was sealed with a septum and placed into the microwave cavity.After the reaction mixture was stirred at 125° C. for 7 min., it waspurified by flash chromatography (dichloromethane:methanol, 85:15) togive 34% (105 mg) of acetic acid2-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-6-(1-oxo-3,4,6,7,8,9-hexahydro-1H-pyrazino[1,2-a]indol-2-yl)-benzylester 113b as solids.

A 100-mL, single-necked, round-bottomed flask equipped with a magneticstirring bar was charged with 113b (105 mg, 0.17 mmol), LiOH.H₂O (35 mg,0.83 mmol), THF (2 mL), isopropanol (2 mL), and water (1 mL). After thereaction mixture was stirred at room temperature for 3 h, it waspartitioned between dichloromethane (5 mL) and water (5 mL), and theorganic phase was extracted with dichloromethane (5 mL×3). The combinedorganic phases were washed with water (5 mL×2) and brine (5 mL×1), dried(Na₂SO₄), and concentrated. The crude product was re-dissolved indichloromethane (3 mL). To this solution was added hexane (10 mL) andthe resulting precipitates were filtered to give 80% yield (79 mg) of2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4,6,7,8,9-hexahydro-2H-pyrazino[1,2-a]indol-1-one113; MS(ESI⁺) m/z 594.3 (M+H).

Example 1142-(3-(6-(1-cyclopropyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one114 Example 114a2-(2-(Acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one114a

To a round-bottomed flask equipped with a stirring bar,2-(3-bromo-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one113a (1.96 g, 4.70 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.79 g,7.05 mmol), Cl₂Pd(dppf)₂.CH₂Cl₂ (306.9 mg, 0.376 mmol), KOAc (4.77 g,18.79 mmol), and dioxane (33.6 mL) were added. The mixture was heated at95° C. overnight. The resulting mixture was filtered through Celite,washed with ethyl acetate (200 mL). The organic phase was washed withwater (50 mL), dried over MgSO₄, and the solvent removed in vacuo toyield the crude product 114a, which was directly used as startingmaterial other syntheses.

Example 114b5-Bromo-3-(1-cyclopropyl-1H-pyrazol-4-ylamino)-1-methylpyrazin-2(1H)-one114b

To a seal tube equipped with a stirring bar,1-cyclopropyl-1H-pyrazol-4-amine (600 mg, 4.87 mmol),3,5-dibromo-1-methylpyrazin-2(1H)-one (1.96 g, 7.31 mmol), Pd₂(dba)₃(223.1 mg, 0.244 mmol), XantPhos (225.5 mg, 0.390 mmol), Cs₂CO₃ (5.25 g,16.08 mmol) and dioxane (12 mL) were added. The tube was sealed andheated at 100° C. overnight. CH₂Cl₂ (200 mL) was added to the resultingmixture, and the CH₂Cl₂ solution was washed with water (30 mL×3). Theprecipitate in the aqueous phase was filtered as pure product 114b. Theorganic phase was dried over MgSO₄, filtered and solvent removed invacuo. CH₂Cl₂/ether (1:2, 3 mL) were added to the residue and themixture was sonicated. The precipitate was filtered, combined with thefiltered solids from the aqueous phase, and dried.5-Bromo-3-(1-cyclopropyl-1H-pyrazol-4-ylamino)-1-methylpyrazin-2(1H)-one114b was obtained as a yellow solid.

Example 114c2-(6-(1-Cyclopropyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 114c

To a microwave tube equipped with a stirring bar, 114b (200 mg, 0.645mmol), 114a (0.903 mmol), Pd(PPh₃)₄, Na₂CO₃ aqueous solution (1.0 N,2.13 mL, 2.13 mmol), DME (2.0 mL) were added. The mixture was reacted inmicrowave at 135° C. for 15 min. DCM (200 mL) was added and theresulting mixture was washed with water (30 mL×3), brine (30 mL×1),dried over MgSO₄, filtered, and removed solvent in vacuo. Silica gelcolumn chromatography (MeOH:DCM=5:95) gave2-(6-(1-cyclopropyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 114c, it was directly used in the next step.

To a round-bottomed flask equipped with a stirring bar, 114c THF (1.25mL), i-PrOH (1.25 mL), H₂O (1.25 mL), LiOH H₂O (135 mg) were added. Theresulting mixture was stirred at RT for 1 hr. Removed all the solvent invacuo and silica gel column chromatography (MeOH:DCM=10:90) gave 38.6 mg2-(3-(6-(1-cyclopropyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-(hydroxymethyl)-phenyl)-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-1(2H)-one114 as a yellow solid. MS (ESI+) m/z 526.3 (M+H).

Example 1155-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-6-one115 Example 115btert-Butyl(2-bromo-4-fluoro-6-(1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzyloxy)dimethylsilane115b

A sealed tube with a magnetic stirrer was charged with 104e (1.11 g,5.37 mmol), 115a (4.24 g, 10.7 mmol), cesium carbonate (3.49 g, 10.7mmol), N,N′-dimethylethylenediamine (0.47 g, 5.37 mmol) and 1,4-dioxane(45 mL). After degassed for 10 minutes, copper iodide (0.51 g, 2.68mmol) was added, and the reaction mixture was heated at 105° C. for 2days. Another portion of N,N′-dimethylethylenediamine (0.47 g, 5.37mmol) and copper iodide (0.51 g, 2.68 mmol) was added, and the reactionmixture was heated at 105° C. for another 5 hours. After this time, themixture was cooled to room temperature and filtered. The filtrate wasdiluted with ethyl acetate (50 mL) and water (40 mL). The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatography(silica, Ethyl Acetate/Hexanes) to afford a 40% yield (1.14 g) ofcompound 115b as a yellow solid: MS (ESI+) m/z 524.1 (M+H).

A 10 mL microwave vial with a magnetic stirrer was charged with 115b(157 mg, 0.3 mmol),1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one109c (148 mg, 0.45 mmol), 1M sodium carbonate solution (1.2 mL, 1.2mmol) and 1,2-Dimethoxyethane (3 mL). After bubbling nitrogen throughthe resulting suspension for 10 min,tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) was added.The reaction mixture was heated at 130° C. for 15 minutes in themicrowave reactor. The reaction was repeated at the same scale, and thereaction mixture was combined. Ethyl Acetate (20 mL) and water (10 mL)were added, and the layers were separated. The aqueous layer wasextracted with Ethyl acetate (2×10 mL), and the combined organic layerswere washed with brine and dried over sodium sulfate. The drying agentwas removed by filtration. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by flash columnchromatography (silica, 60:35:5 methylene chloride/ether/methanol) togive 400 mg mixture of compounds 115c and 115 as a yellow residue. Theabove residue was dissolved in methanol (5 mL). 10-Camphorsulfonic acid(350 mg, 1.5 mmol) was added, and the mixture was stirred at roomtemperature for 1 h. After this time, the mixture was basified withsaturated sodium bicarbonate. The aqueous layer was extracted withmethylene chloride (2×10 mL), and the combined organic layers werewashed with brine and dried over sodium sulfate. The drying agent wasremoved by filtration. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by flash columnchromatography (NH-silica, Ethyl acetate/Hexanes) to afford a 33% yield(88 mg) of compound 115 as a pale yellow solid: MS (ESI+) m/z 532.2(M+H)

Example 1165-[3-(6-{[1-(2-Hydroxyethyl)-1H-pyrazol-4-yl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-(hydroxymethyl)phenyl]-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-6-one116 Example 116a1-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-nitro-1H-pyrazole 116a

A 100-mL single-neck round-bottomed flask equipped with a refluxcondenser and magnetic stirrer was purged with nitrogen and charged with4-nitro-1H-pyrazole (500 mg, 4.42 mmol),(2-bromoethoxy)(tert-butyl)dimethylsilane (2.12 g, 8.85 mmol), cesiumcarbonate (5.76 g, 17.7 mmol) and anhydrous DMF (5 mL). After heating at70° C. for 1 h, the mixture was cooled to room temperature and dilutedwith methylene chloride (50 mL) and water (30 mL). The organic layer wasseparated, and the aqueous layer was extracted with methylene chloride(2×30 mL). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure. The residue was purified bycolumn chromatography to afford a 92% yield (1.11 g) of 116a as a whitesolid: mp 63-64° C.; ¹H NMR (500 MHz, CDCl₃) d 8.20 (s, 1H), 8.08 (s,1H), 4.24 (t, 2H, J=4.5 Hz), 3.95 (t, 2H, J=4.5 Hz), 0.84 (s, 9H), −0.04(s, 6H).

Example 116b 1-(2-(tert-Butyldimethylsilyloxy)ethyl)-1H-pyrazol-4-amine116b

A 250-mL Parr reactor bottle was purged with nitrogen and charged with10% palladium on carbon (50% wet, 150 mg dry weight) and a solution of116a (1.11 g, 4.10 mmol) in ethanol (20 mL). The bottle was attached toa Parr hydrogenator, evacuated, charged with hydrogen gas to a pressureof 50 psi and shaken for 3 h. After this time, the hydrogen wasevacuated, and nitrogen was charged into the bottle. Celite 521 (1.00 g)was added, and the mixture was filtered through a pad of Celite 521. Thefilter cake was washed with ethanol (2×25 mL), and the combinedfiltrates were concentrated to dryness under reduced pressure to afforda 100% yield of 116b (985 mg) as an orange oil: ¹H NMR (500 MHz, CDCl₃)d 7.18 (s, 1H), 7.11 (s, 1H), 4.09 (t, 2H, J=5.5 Hz), 3.89 (t, 2H, J=5.5Hz), 3.25 (br s, 2H), 0.86 (s, 9H), −0.32 (s, 6H). MS (ESI+) m/z 242.2(M+H).

Example 116c5-Bromo-3-(1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-4-ylamino)-1-methylpyrazin-2(1H)-one116c

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 116b(400 mg, 1.66 mmol), 3,5-dibromo-1-methyl pyrazin-2(1H)-one (443 mg,1.66 mmol), cesium carbonate (1.19 g, 3.65 mmol), and 1,4-dioxane (20mL). After bubbling nitrogen through the resulting suspension for 30min, Xantphos (144 mg, 0.249 mmol) andtris(dibenzylideneacetone)-dipalladium(0) (152 mg, 0.166 mmol) wereadded, and the reaction mixture was heated at reflux for 4 h. After thistime, the mixture was cooled to room temperature and filtered, and thefilter cake was washed with methylene chloride (2×20 mL). The filtrateswere combined and concentrated under reduced pressure, and the resultingresidue was purified by column chromatography to afford a 51% yield (353mg) of 116c as a yellow solid: mp 172-173° C.; ¹H NMR (500 MHz, CDCl₃) d8.17 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 6.70 (s, 1H), 4.28 (t, 2H,J=5.0 Hz), 3.97 (t, 2H, J=5.5 Hz), 3.51 (s, 3H), 0.85 (s, 9H), −0.79 (s,6H); MS (APCI+) m/z 428.3 (M+H).

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with116c (150 mg, 0.312 mmol), 111a (133 mg, 0.312 mmol), sodium carbonate(99 mg, 0.936 mmol), 1,4-dioxane (5 mL) and water (1 mL). This mixturewas degassed with nitrogen for 30 min.Tetrakis-(triphenyl-phosphine)palladium (36 mg, 0.031 mmol) was added.After heating at 100° C. for 3 h, the reaction mixture was cooled toroom temperature and partitioned between water (40 mL) and methylenechloride (100 mL). The layers were separated, and the aqueous phase wasextracted with methylene chloride (2×50 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was dissolved in methanol (5mL), and potassium carbonate (500 mg, 3.62 mmol) was added. Afterstirring at room temperature for 2 h, the reaction mixture waspartitioned between water (20 mL) and methylene chloride (20 mL). Thelayers were separated, and the aqueous phase was extracted withmethylene chloride (2×20 mL). The organic extracts were combined, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was redissolved in THF (5 mL), andtetrabutylammonium fluoride trihydrate (500 mg, 1.58 mmol) was added.After stirring at room temperature for 3 h, the solvent was removedunder reduced pressure, and the resulting residue was washed with water(10 mL). The resulting solid was purified by flash chromatography toafford 116 in 27% yield (47 mg) as an off-white solid: mp 171-172° C.;¹H NMR (500 MHz, DMSO-d₆) δ 9.56 (s, 1H), 8.16 (s, 1H), 7.75 (s, 1H),7.58 (d, 1H, J=8.0 Hz), 7.44 (t, 1H, J=8.0 Hz), 7.33-7.32 (m, 2H), 4.86(m, 1H), 4.81 (t, 1H, J=5.5 Hz), 4.51 (dd, 1H, J=11.0, 6.5 Hz), 4.44(dd, 1H, J=11.0, 6.5 Hz), 4.06 (t, 2H, J=5.5 Hz), 4.02 (m, 1H), 3.68 (t,2H, J=5.5 Hz), 3.88 (m, 1H), 3.68 (q, 2H, J=5.5 Hz), 3.52 (s, 3H), 2.98(m, 1H), 2.86 (m, 1H), 2.77 (m, 2H), 2.58-2.46 (m, 2H), 1.79 (m, 4H); MS(APCI+) m/z 547.2 (M+H)

Example 1172-(2-methyl-3-(5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one117 Example 117a9-((2-(Trimethylsilyl)ethoxy)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one117a

A 25-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with anhydrous DMF (4 mL)and a 60% dispersion of sodium hydride in mineral oil (181 mg, 4.52mmol) and the reaction mixture was cooled to 0° C.1,2,3,4-tetrahydro-1-oxo-beta-carboline (841 mg, 4.52 mmol) was added,and the reaction was stirred at 0° C. for 15 min. After this time,2-(trimethylsilyl)ethoxymethyl chloride (829 mg, 4.97 mmol) was added,and the reaction was stirred at 0° C. for 1 h. The reaction mixture wasthen partitioned between water (10 mL) and ethyl acetate (20 mL). Thelayers were separated, and the aqueous phase was extracted with ethylacetate (2×10 mL). The organic extracts were combined, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by flash chromatography to afford 117a in 57% yield(818 mg) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) d 7.67 (d, 1H,J=8.0 Hz), 7.65 (d, 1H, J=8.0 Hz), 7.46 (t, 1H, J=8.0 Hz), 7.27 (t, 1H,J=8.0 Hz), 6.14 (s, 2H), 5.72 (br s, 1H), 3.75 (t, 2H, J=7.0 Hz), 3.66(t, 2H, J=8.0 Hz), 3.14 (t, 2H, J=7.0 Hz), 0.96 (t, 2H, J=8.0 Hz), −0.25(s, 9H).

Example 117b2-(3-Bromo-2-methylphenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one117b

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 117a (400 mg, 1.27 mmol),2,6-dibromotoluene (633 mg, 2.53 mmol), cesium carbonate (828 mg, 2.54mmol), N-methylethylenediamine (112 mg, 1.27 mmol) and 1,4-dioxane (20mL). After bubbling nitrogen through the resulting suspension for 30min, copper iodide (121 mg, 2.54 mmol) was added. A reflux condenser wasattached to the flask, and the reaction mixture was heated at 100° C.for 16 h. After this time, the mixture was cooled to room temperatureand filtered. The filtrate was concentrated under reduced pressure, andthe resulting residue was purified by flash column to afford 117b in 41%yield (251 mg) as a yellow oil: ¹H NMR (500 MHz, CDCl₃) d 7.71 (d, 1H,J=8.0 Hz), 7.68 (d, 1H, J=8.0 Hz), 7.63 (d, 1H, J=8.0 Hz), 7.47 (t, 1H,J=8.0 Hz), 7.32-7.28 (m, 2H), 7.21 (t, 1H, J=8.0 Hz), 6.13 (s, 2H), 4.15(m, 1H), 3.93 (m, 1H), 3.69 (m, 2H), 3.29 (m, 2H), 2.45 (s, 3H), 0.95(t, 2H, J=8.0 Hz), −0.07 (s, 9H).

Example 117c2-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one117c

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and nitrogen inlet was charged with 117b (250mg, 0.515 mmol),4,4,4′,4′,-5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (157 mg,0.619 mmol), potassium acetate (152 mg, 1.55 mmol) and 1,4-dioxane (5mL). After bubbling nitrogen through the resulting suspension for 30min, [1,1-Bis(diphenylphosphino)ferrocene]-dichloro-palladium(II)/CH₂Cl₂(38 mg, 0.052 mmol) was added, and the reaction mixture was heated at95° C. for 5 h. After this time, the mixture was diluted with ethylacetate (20 mL) and water (20 mL), and the layers were separated. Theaqueous layer was extracted with ethyl acetate (50 mL), and the combinedorganic layers were washed with brine (50 mL) and dried over sodiumsulfate. The drying agent was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by flash column chromatography to afford 117c in 97% yield (242mg) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) d 7.85 (d, 1H, J=8.0Hz), 7.72 (d, 1H, J=8.0 Hz), 7.68 (d, 1H, J=8.0 Hz), 7.46 (t, 1H, J=8.0Hz), 7.39-7.28 (m, 2H), 7.21 (t, 1H, J=8.0 Hz), 6.19 (d, 1H, J=10.5 Hz),6.15 (d, 1H, J=10.5 Hz), 4.16 (m, 1H), 3.97 (m, 1H), 3.68 (m, 2H), 3.29(m, 2H), 2.45 (s, 3H), 0.95 (t, 2H, J=8.0 Hz), 1.34 (s, 12H), −0.07 (s,9H).

Example 117d4-Bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one117d

A 500-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with anhydrous DMF (150 mL)and 4-bromo-6-chloro-pyridazin-3(2H)-one (10.0 g, 47.8 mmol). Thereaction mixture was cooled to 0° C. and sodium hydride was added. Thereaction was stirred at 0° C. for 20 min. After this time,2-(Trimethylsilyl)ethoxymethyl chloride (11.9 g, 71.6 mmol) was addedand the cooling bath was removed, and the reaction was stirred at roomtemperature for 3 h. The reaction was then quenched with saturatedaqueous sodium bicarbonate (30 mL). The mixture was extracted with ethylacetate (2×300 mL). The extracts were dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography to afford 117d in a 56% yield (9.00g) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) d 8.02 (s, 1H), 5.42 (s,2H), 3.79 (t, 2H, J=5.4 Hz), 0.96 (t, 2H, J=5.4 Hz), 0.01 (s, 9H).

Example 117e6-Chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one117e

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 117d (1.12 g, 3.29 mmol),103e (500 mg, 3.29 mmol), cesium carbonate (3.22 g, 9.87 mmol) and1,4-dioxane (25 mL). After bubbling nitrogen through the resultingsolution for 30 min, Xantphos (286 mg, 0.494 mmol) andtris(dibenzylideneacetone)dipalladium(0) (301 mg, 0.329 mmol) were addedand the reaction mixture was heated at reflux for 3 h. After this time,the reaction mixture was cooled to room temperature and partitionedbetween water (30 mL) and methylene chloride (60 mL). The layers wereseparated, and the aqueous phase was extracted with methylene chloride(60 mL). The organic extracts were combined, dried over sodium sulfateand filtered, and the solvent was removed from the filtrate underreduced pressure. The resulting residue was purified by columnchromatography to afford a 72% yield (977 mg) of 117e as a yellow solid:mp 68-69° C.; ¹H NMR (500 MHz, CDCl₃) d 7.85 (s, 1H), 7.56 (s, 1H), 5.70(s, 1H), 5.47 (s, 2H), 4.16 (t, 2H, J=5.5 Hz), 3.73 (m, 2H), 3.63 (s,2H), 2.94 (t, 2H, J=5.5 Hz), 2.51 (s, 3H), 0.98 (m, 2H), 0.12 (s, 9H);MS (ESI+) m/z 411.2 (M+H).

Example 117f2-(2-Methyl-3-(5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)phenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one117f

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and nitrogen inlet was charged with1,4-dioxane (5 mL), water (1 mL) and sodium carbonate (143 mg, 1.35mmol). After bubbling nitrogen through the resulting mixture for 30 min,117c (240 mg, 0.451 mmol), 117e (185 mg, 0.451 mmol) andtetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) were added,and the reaction mixture was heated at 100° C. for 3 h. After this time,the reaction was cooled to room temperature and partitioned betweenwater (25 mL) and methylene chloride (50 mL). The organic layer wasseparated, washed with brine (75 mL) and dried over sodium sulfate. Thedrying agent was removed by filtration, and the filtrate wasconcentrated under reduced pressure to a dark oil, which was purified byflash chromatography to afford an 89% yield (315 mg) of 117f as a yellowoil: ¹H NMR (500 MHz, CDCl₃) d 7.88 (s, 1H), 7.66 (d, 1H, J=8.0 Hz),7.45 (m, 3H), 7.39 (t, 1H, J=8.0 Hz), 7.34 (d, 1H, J=8.0 Hz), 7.24 (t,2H, J=8.0 Hz), 6.12 (d, 1H, J=10.5 Hz), 6.05 (d, 1H, J=10.5 Hz), 5.69(s, 1H), 5.63 (d, 1H, J=10.5 Hz), 5.52 (d, 1H, J=10.5 Hz), 4.09 (m, 2H),3.88 (m, 2H), 3.75 (m, 2H), 3.68 (s, 3H), 3.59 (m, 2H), 3.26-3.17 (m,4H), 2.61 (m, 2H), 2.29 (s, 3H), 0.98 (t, 2H, J=8.0 Hz), 0.85 (t, 2H,J=8.0 Hz), −0.01 (s, 9H), −0.07 (s, 9H); MS (ESI+) m/z 781.4 (M+H).

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 117f (315 mg, 0.404mmol), anisole (438 mg, 4.04 mmol), methylene chloride (3 mL) andtrifluoroacetic acid (3 mL). After stirring at room temperature for 2 h,the reaction mixture was concentrated, and the resulting residue waspartitioned between 1 M aqueous potassium dihydrogen phosphate (10 mL)and methylene chloride (20 mL). The layers were separated, and theaqueous phase was extracted with methylene chloride (2×10 mL). Theorganic extracts were combined and dried over sodium sulfate, filteredand concentrated under reduced pressure. The resulting residue waspurified by flash chromatography to afford 117 in 23% yield (49 mg) as awhite solid: mp 254° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 12.97 (s, 1H),11.74 (s, 1H), 9.21 (s, 1H), 7.79 (s, 1H), 7.65 (d, 1H, J=8.0 Hz),7.44-7.37 (m, 3H), 7.34 (d, 1H, J=8.0 Hz), 7.26 (t, 1H, J=8.0 Hz), 7.08(t, 1H, J=8.0 Hz), 5.75 (s, 1H), 4.17 (m, 1H), 3.97 (t, 2H, J=5.0 Hz),3.84 (m, 1H), 3.51 (s, 2H), 3.17 (m, 2H), 2.79 (t, 2H, J=5.0 Hz), 2.35(s, 3H), 2.18 (s, 3H); MS (ESI+) m/z 521.2 (M+H)

Example 1182-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one118 Example 118a Methyl 5,6,7,8-Tetrahydroindolizine-2-carboxylate 118a

A 500-mL round-bottomed flask equipped with a magnetic stirrer andnitrogen inlet was purged with nitrogen and charged with5,6,7,8-tetrahydroindolizine-2-carboxylic acid (30.4 g, 184 mmol), DMF(1.00 g, 13.6 mmol) and methylene chloride (300 mL). The solution wascooled to 0° C. using an ice bath. Oxalyl chloride (28.0 g, 221 mmol)was added dropwise, and the reaction mixture was warmed to roomtemperature over 30 min and stirred for 5 h. After this time, theresulting solution was concentrated to afford a brown solid. This solidwas dissolved in anhydrous methanol (400 mL), and the solution wascooled to 0° C. Triethylamine (57 g, 552 mmol) was added to the reactionmixture, and it was stirred for a further 2 h at room temperature. Afterthis time, the reaction mixture was concentrated to dryness underreduced pressure. The residue was diluted with methylene chloride (300mL) and washed with water (200 mL) and saturated aqueous sodiumbicarbonate (200 mL). The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas titrated with hexane (200 mL) to afford 118a in 58% yield (19.1 g)as a white solid: mp 72-74° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.13 (s,1H), 6.23 (s, 1H), 3.93 (t, 2H, J=6.0 Hz), 3.77 (s, 3H), 2.75 (t, 2H,J=6.0 Hz), 1.93 (m, 2H), 1.80 (m, 2H); (APCI+) m/z 180.1 (M+H)

Example 118b Methyl3-(Cyanomethyl)-5,6,7,8-tetrahydroindolizine-2-carboxylate 118b

A 500-mL three-neck round-bottomed flask equipped with an additionfunnel, thermometer and charged with 118a (6.70 g, 37.4 mmol),Iodoacetonitrile (12.5 g, 74.9 mmol), iron (II) sulfate heptahydrate(5.20 g, 18.7 mmol) and dimethyl sulfoxide (250 mL). Hydrogen peroxide(35%, 18.2 g, 187 mmol) was added dropwise to the mixture in 1 h througha syringe pump at room temperature using a water bath. Iron (II) sulfateheptahydrate (2 to 3 equivalent) was added to the reaction mixture inportions to keep the temperature between 25° C. to 35° C., until thecolor of the reaction mixture is deep red. If TLC show the reaction notcompleted, then more hydrogen peroxide (2-3 equivalent) and more iron(II) sulfate heptahydrate (1-2 equivalent) were added in the same manneruntil the reaction is completed. After that time, the reaction mixturewas partitioned between saturated sodium bicarbonate solution (200 mL)and ethyl acetate (400 mL). The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with saturated Sodium thiosulfate solution(50 mL), dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography to afford a78% yield (6.40 g) of 118b as a yellow oil: ¹H NMR (500 MHz, CDCl₃) d6.23 (s, 1H), 4.23 (s, 2H), 3.94 (t, 2H, J=6.5 Hz), 3.81 (s, 3H), 2.74(t, 2H, J=6.5 Hz), 2.00 (m, 2H), 1.83 (m, 2H); (APCI+) m/z 219.3 (M+H)

Example 118c Methyl3-(2-Aminoethyl)-5,6,7,8-tetrahydroindolizine-2-carboxylate HydrogenChloride Salt 118c

Intermediate 118b was hydrogenated with platinum oxide catalyst under 50psi of hydrogen in ethanol and ethyl acetate in the presence of hydrogenchloride overnight at room temperature to give 118c (380 mg, 1.74 mmol)which was used in directly in the next step.

Example 118d 3,4,6,7,8,9-Hexahydropyrido[3,4-b]indolizin-1(2H)-one 118d

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was purged with nitrogen and charged withmethyl 3-(2-aminoethyl)-5,6,7,8-tetrahydroindolizine-2-carboxylatehydrogen chloride salt 118c (estimated 1.74 mmol, presuming quantitativeyield), sodium ethoxide (354 mg, 5.22 mmol) and ethanol (20 mL). Themixture was stirred at 55° C. for 5 h. After that time, the reactionmixture was concentrated under reduced pressure and the residue waspartitioned between ethyl acetate (200 mL) and water (100 mL). Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (2×100 mL). The combined organic layers were washed withbrine, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography to afford a67% yield (220 mg) of 118d as a white solid: mp 195-197° C.; ¹H NMR (500MHz, DMSO-d₆) δ 6.76 (s, 1H), 5.89 (s, 1H), 3.78 (t, 2H, J=6.5 Hz), 3.35(m, 2H), 2.66 (m, 4H), 1.87 (m, 2H), 1.72 (m, 2H); (APCI+) m/z 191.3(M+H)

Example 118e2-Bromo-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)benzylAcetate 118e

A 250-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer was purged with nitrogen and charged with118d (1.50 g, 7.89 mmol), 2,6-dibromobenzyl acetate 104g (4.80 g, 15.7mmol), cesium carbonate (5.11 g, 15.7 mmol),N,N′-dimethylethylenediamine (695 mg, 7.89 mmol), and 1,4-dioxane (100mL). After bubbling nitrogen through the resulting suspension for 20min, copper iodide (752 mg, 3.95 mmol) was added, and the reactionmixture was heated at 95° C. (oil bath temperature) for 12 h. And thenN,N′-dimethylethylenediamine (695 mg, 7.89 mmol) and copper iodide (752mg, 3.95 mmol) were added and heated at 95° C. for another 12 h,repeated this until most of 118d was converted to 118e, about 48 h.After this time, the mixture was cooled to room temperature andfiltered. The filtrate was diluted with ethyl acetate (300 mL) and water(100 mL). The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by flash chromatography to afford a 27% yield(905 mg) of 118e as an off-white solid: mp 176-178° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.64 (dd, 1H, J=7.5, 1.8 Hz), 7.37 (m, 2H), 5.99 (s, 1H),5.00 (d, 2H, J=6.0 Hz), 4.00 (m, 1H), 3.85 (m, 2H), 3.62 (m, 1H), 2.93(t, 2H, J=6.1 Hz), 2.67 (t, 2H, J=6.1 Hz), 2.00 (d, 3H, J=6.0 Hz), 1.90(m, 2H), 1.75 (m, 2H); MS (ESI+) m/z 417.0 (M+H)

Example 118f2-(1-Oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylAcetate 118f

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 118e(1.20 g, 2.88 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.20 g,8.65 mmol), potassium acetate (1.13 g, 11.5 mmol) and 1,4-dioxane (50mL). After bubbling nitrogen through the resulting suspension for 20min, [1,1-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (210mg, 0.288 mmol) was added, and the reaction mixture was heated at 95° C.for 8 h. After this time, the mixture was cooled to room temperature andfiltered. The filter cake was washed with ethyl acetate (40 mL). Thefiltrate was diluted with ethyl acetate (150 mL) and water (40 mL). Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (3×50 mL). The combined organic layers were dried oversodium sulfate and concentrated under reduced pressure to afford a 100%yield (1.35 g) of crude 118f as a yellow oil.

A 100-mL three-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 118f (400 mg, 0.862 mmol),5-bromo-1-methyl-3-(pyrimidin-4-ylamino)pyridin-2(1H)-one 109b (241 mg,0.862 mmol), sodium carbonate (365 mg, 3.45 mmol), water (4 mL) and1,4-dioxane (20 mL). After bubbling nitrogen through the resultingsuspension for 20 min, tetrakis(triphenylphosphine)-palladium(0) (100mg, 0.086 mmol) was added, and the reaction mixture was heated at 100°C. for 2 h. After this time, the reaction mixture was cooled to roomtemperature and filtered, and the filter cake was washed with a 1:10mixture of methanol and methylene chloride (30 mL). The filtrate wasconcentrated under reduced pressure to afford a brown residue. Another50-mL single-neck round-bottomed flask equipped with a magnetic stirrerand reflux condenser was charged with residue obtained above, THF (5mL), ethanol (5 mL), water (5 mL) and lithium hydroxide (83.0 mg, 3.45mmol). The mixture was stirred at 50° C. for 2 h. After this time, thereaction mixture was concentrated under reduced pressure. The resultingresidue was purified by flash chromatography to afford a 23% (106 mg)yield of 118 as an off-white solid: mp 173-175° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 7.16 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.29 (d, 1H, J=6.0Hz), 7.55 (s, 1H), 7.45 (t, 1H, J=7.5 Hz), 7.29 (m, 3H), 6.00 (s, 1H),4.75 (t, 1H, J=5.0 Hz), 4.31 (d, 2H, J=5.0 Hz), 4.00 (m, 1H), 3.96 (m,1H), 3.81 (m, 2H), 3.60 (s, 3H), 3.00 (m, 1H), 2.91 (m, 1H), 2.71 (t,2H, J=5.5 Hz), 1.92 (m, 2H), 1.75 (m, 2H); MS (ESI+) m/z 497.2 (M+H)

Example 1195-[2-(Hydroxymethyl)-3-(5-{[5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one119 Example 119a Methyl 3-Amino-1-methyl-1H-pyrazole-5-carboxylate 119a

In a 250 mL Parr hydrogenation flask was placed methyl1-methyl-3-nitro-1H-pyrazole-5-carboxylate, (530 mg, 2.9 mmol) dissolvedin ethyl acetate (15 mL) and ethanol (15 mL), to which was added 10%Pd/C (Degussa type) (100 mg). The mixture was placed on the Parrapparatus and pressurized with hydrogen to 50 PSI and shaken for 2.5hrs. The reaction was filtered through a pad of celite which was washedwith ethyl acetate. The solvent was removed under vacuum to give 119a asa white solid (450 mg, 2.9 mmol, quantitative yield).

Example 119b Methyl3-(6-Chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-1-methyl-1H-pyrazole-5-carboxylate119b

In a 3-neck RBF was placed 119a (500 mg, 3.2 mmol),4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (725 mg, 3.2 mmol), cesiumcarbonate (2.3 g, 7.0 mmol), and Xantphos (160 mg, 8.5 mol %). The flaskwas evacuated and filled with nitrogen 3×. Dioxane (20 ml) was added andthe mixture degassed for 25 min with bubbling nitrogen.Tris(dibenzylideneacetone)dipalladium(0) (150 mg, 5 mol %) was thenadded and the reaction heated to 100° C. for 6 hrs. The reaction wascooled and diluted with EtOAc (125 mL) and saturated aqueous NaHCO3 (50mL), the layers were separated and extracted EtOAc (2×100 mL). Theorganics were washed with brine 3×, dried over Na2SO4, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography: ISCO 40 g silica, EtOAc/hexanes, to give 119b.

Example 119c6-Chloro-4-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one119c

In a 100 mL round bottom flask containing 119b (500 mg, 1.7 mmol) undernitrogen was added anh. THF (20 mL) and anh.toluene (5 mL) and themixture stirred and cooled to −20 to −30° C. 3.0M methylmagnesiumbromide in diethylether (1.6 mL, 4.75 mmol) was then slowly added. Afterthe addition the reaction was allowed to slowly warm to room temp. andstir for about 3 hrs after which the reaction was quenched with 1N HCl.Concentrated to remove THF, diluted with ethyl acetate and water thenadjusted the pH to ˜6-7 with 1M NaOH. Separated and extracted 2× withethyl acetate washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography: ISCO 24 g silica, ethyl acetate/hexanes, to give 119c.

Example 119d2-(5-(5-(2-Hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 119d

In a microwave vial was placed 119c (150 mg, 0.50 mmol) and 111a (240mg, 0.50 mmol) and DME (4 mL) was added followed by 1N Na₂CO₃ (1.1 mL).After degassing with bubbling argon for 5 min,tetrakis(triphenylphosphine)palladium(0) (29 mg, 5 mol %) was added andthe mixture was heated in a microwave reactor at 130° C. for 15 min. Anadditional 40 mg 111a was added and the mixture heated an additional 10min. The reaction was diluted with ethyl acetate and water, the ethylacetate layer separated, washed with brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bychromatography: ISCO 12 g silica, eluting with methanol and CH₂Cl₂, togive 119d (170 mg, 56% yield).

To a vial containing 119d (170 mg, 0.28 mmol) dissolved in THF (1.5 mL)and I-propanol (1.5 ml) was added 1N LiOH/water (1.4 mL, 1.4 mmol) andthe mixture stirred overnight after with the reaction was judgedcomplete by LC-MS. The mixture was concentrated then diluted with ethylacetate and water and 1N HCl and 1N NaOH were added to adjust the pH to7. The ethyl acetate layer was separated, washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas triturated with ethyl acetate and the solids collected by filtrationto give 119 (98 mg, 61% yield). MS (ESI+) m/z 575.2 (M+H).

Example 1205-[5-Fluoro-2-(hydroxymethyl)-3-[4-methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one120 Example 120a tert-Butyl6-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate120a

A mixture of tert-butyl6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (3 g, 12 mmol),3,5-dibromo-1-methylpyrazin-2(1H)-one (2.68 g, 10 mmol), andtriethylamine (1.5 g, 15 mmol) in IPA (50 mL) was heated at 70° C. for15 h. The mixture was cooled to room temperature. The resulting yellowsolids were collected by filtration and dried in vacuum to afford 120aas a yellow solid (2.83 g, 65%). MS: [M+H]⁺ 435.

Example 120b4-Fluoro-2-[4-methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2-yl]-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl}methylacetate 120b

Following Example 150b, 482 mg of 218b and 435 mg of 120a were reactedto give 362 mg (51%) of 120b as a yellow solid MS: [M+H]⁺ 711.

Following Example 149, 200 mg of 120b was converted to 120 as a whitesolid (78 mg, 42%). ¹H NMR (500 MHz, MeOD) δ 7.72 (s, 1H), 7.58 (d,J=8.0, 1H), 7.39 (m, 2H), 7.21 (ss, J=9.5, 1H), 7.10 (d, J=8.5, 1H),4.62 (d, J=12, 1H), 4.50 (d, J=12, 1H), 4.11 (m, 3H), 3.98 (m, 1H), 3.64(s, 3H), 3.28 (s, 2H), 2.95 (m, 4H), 2.85 (s, 2H), 2.60 (m, 2H), 1.9 (m,4H).

Example 1215-[2-(Hydroxymethyl)-3-(4-methyl-5-oxo-6-{[4-(piperidin-4-yl)phenyl]-amino}-4,5-dihydropyrazin-2-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one121 Example 121a tert-Butyl4-(4-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-piperidine-1-carboxylate121a

Compound 121a was synthesized using the same procedure as example 112a,except using tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (0.83g, 3.0 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (0.88 g, 3.3 mmol),cesium carbonate (1.27 g, 3.9 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.275 g, 0.3 mmol), Xantphos(0.26 g, 0.45 mmol) and 1,4-dioxane (30 mL). The reaction mixture washeated at 100° C. overnight. Work-up and purified by flash columnchromatography (silica, ethyl acetate/hexanes) to give a 80% yield (1.1g) of 121a as a solid: MS (ESI+) m/z 465.0 (M+H).

Example 121b5-[2-(Acetoxymethyl)-3-(4-methyl-5-oxo-6-{[4-(piperidin-4-yl)phenyl]-amino}-4,5-dihydropyrazin-2-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one121b

A 10 mL microwave vial with a magnetic stirrer was charged with 111a(173 mg, 0.36 mmol), 121a (139 mg, 0.3 mmol), 1M sodium carbonatesolution (1.2 mL, 1.2 mmol) and 1,2-dimethoxyethane (3 mL). Afterbubbling nitrogen through the resulting suspension for 10 min,tetrakis(triphenylphosphine)-palladium(0) (18 mg, 0.015 mmol) was added.The reaction mixture was heated at 130° C. for 15 minutes in themicrowave reactor. After this time, ethyl acetate (15 mL) and water (10mL) were added, and the layers were separated. The aqueous layer wasextracted with Ethyl acetate (2×20 mL), and the combined organic layerswere washed with brine and dried over sodium sulfate. The drying agentwas removed by filtration. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by flash columnchromatography (silica, ethyl acetate/hexanes) to afford compound 121bas yellow oil (240 mg).

Compound 121b was dissolved in methylene chloride (10 mL).Trifluoroacetic acid (0.3 mL, 3.9 mmol) was added, and the mixture wasstirred at room temperature for 4 h. After this time, the mixture wasbasified by saturated sodium bicarbonate, and the aqueous layer wasextracted with methylene chloride (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. The drying agentwas removed by filtration. The filtrate was concentrated, and theresulting residue 121c was dissolved in a mixture of THF (1.5 mL), water(0.8 mL) and isopropanol (1.5 mL). Lithium hydroxide monohydrate (56 mg,1.32 mmol) was added, and the mixture was stirred at room temperaturefor 3 h. After this time, the mixture was diluted with 90:10 methylenechloride/methanol (10 mL) and water (5 mL), and the layers wereseparated. The aqueous layer was extracted with 90:10 methylenechloride/methanol (2×10 mL), and the combined organic layers were washedwith brine and dried over sodium sulfate. The drying agent was removedby filtration. The filtrate was purified by flash column chromatography(silica, methylene chloride/methanol) to afford a 35% yield (3 steps, 63mg) of compound 121 as a light pink solid: MS (ESI+) m/z 596.3 (M+H).

Example 1225-[5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-{[4-(morpholin-4-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one122 Example 122a 5-Bromo-1-methyl-3-(4-morpholinophenylamino)pyrazin-2(1H)-one (3-3) 122a

A microwave vial equipped with a magnetic stirrer was charged with3,5-dibromo-1-methylpyrazin-2(1H)-one (1.97 g, 7.4 mmol),4-morpholinobenzenamine (1.97 g, 11.1 mmol), and isopropanol (25 mL).The system was evacuated and then refilled with N₂. It was heated at 90°C. for 16 h. Then, the mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography eluting with 5:1 petroleum ether/ethyl acetate toafford 122a (2.3 g, 85%). LCMS: [M+H]⁺ 365.

Example 122b4-Methyl-6-(4-morpholinophenylamino)-5-oxo-4,5-dihydropyrazin-2-ylboronicAcid 122b

A microwave vial equipped with a magnetic stirrer was charged with 122a(764 mg, 2.1 mmol), (PinB)₂ (2.75 g, 10 mmol), Pd(dppf)Cl₂ (0.1 g, 0.13mmol), KOAc (0.6 g, 6 mmol), and DMF (5 mL). The system was evacuatedand then refilled with N₂. The reaction mixture was then heated at 105°C. for 1 h, then cooled to room temperature and filtered. The filtratewas concentrated under reduced pressure to give the crude 122b, whichwas used without further purification. LCMS: [M+H]⁺ 331.

Example 122c[4-Fluoro-2-(4-methyl-6-{[4-(morpholin-4-yl)phenyl]amino}-5-oxopyrazin-2-yl)-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 122c

A 25 mL vial was charged with(2-bromo-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl)methylacetate 212a (300 mg, 0.67 mmol), 122b (440 mg, 1.33 mmol) suspended in1,2-dimethoxyethane (15 mL) and water (1 mL). The resulting orangesolution was heated for 30 minutes in a Biotage microwave reactor heldat a constant temperature of 130° C. After reaction the residue waspurified by reverse phase Combi-flash eluting with 0.3% NH₄HCO₃ in 1:6water/CH₃CN to 122c as a brown solid (200 mg, 46%). MS: (M+H)⁺ 658.

To a solution of 122c (220 mg, 0.33 mmol) in propan-2-ol (7 mL),tetrahydrofuran (7 mL), and water (2 mL) was added LiOH (804 mg, 33mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedunder reduced pressure and the residue was purified by prep-HPLC toafford 122 as a yellow solid (82 mg, 40%). MS: (M+H)⁺ 616. ¹H NMR (500MHz, MeOD) δ 1.89 (s, 5H), 2.55-2.63 (m, 2H), 2.94 (s, 2H), 3.11-3.13(t, 5H), 3.64 (s, 3H), 3.82-3.84 (t, 4H), 3.93-3.98 (m, 1H), 4.07-4.14(m, 1H), 4.43-4.53 (m, 2H), 6.97-6.99 (d, 2H), 7.18-7.20 (d, 1H), 7.29(s, 1H), 7.36-7.38 (d, 1H), 7.62-7.64 (d, 2H).

Example 1235-(3-{5-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-2-(hydroxymethyl)phenyl)-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one123 Example 123a 1-Cyclopropyl-3-nitro-1H-pyrazole 123a

A 250-mL three-neck round-bottomed flask equipped with a refluxcondenser and magnetic stirrer was purged with nitrogen and charged with3-nitro-(1H)pyrazole (1.30 g, 11.5 mmol), cyclopropylboronic acid (1.98g, 23.0 mmol), sodium carbonate (3.66 g, 34.5 mmol), 2,2′-bipyridyl(3.58 g, 23.0 mmol), dichloroethane (60 mL) and copper(II) acetate (2.08g, 11.5 mmol). The reaction mixture was heated at 70° C. (oil bathtemperature) for 3 h. After this time, another portion of cyclopropylboronic acid (1.98 g, 23.0 mmol) was added, and the mixture was heatedfor 3 h. After this time, the mixture was cooled to room temperature andfiltered. The filtrate was diluted with ethyl acetate (350 mL) and water(40 mL). The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate (3×150 mL). The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography (silica, 0% to 100%ethyl acetate/hexanes) to afford an 85% yield (1.49 g) of 123a as acolorless oil: ¹H NMR (500 MHz, CDCl₃) d 7.53 (d, 1H, J=2.4 Hz), 6.87(d, 1H, J=2.5 Hz), 3.71 (m, 1H), 1.25 (m, 2H), 1.12 (m, 2H); MS (APCI+)m/z 154.1 (M+H).

Example 123b 1-Cyclopropyl-1H-pyrazol-3-amine 123b

A 250-mL Parr reactor bottle was purged with nitrogen and charged with10% palladium on carbon (50% wet, 137 mg dry weight) and a solution of123a (600 mg, 3.92 mmol) in ethanol (70 mL). The bottle was attached toa Parr hydrogenator, evacuated, charged with hydrogen gas to a pressureof 50 psi and shaken for 3 h. After this time, the hydrogen wasevacuated, and nitrogen was charged into the bottle. Celite 521 (1.00 g)was added, and the mixture was filtered through a pad of Celite 521. Thefilter cake was washed with ethanol (2×25 mL), and the combinedfiltrates were concentrated to dryness under reduced pressure to afforda 93% yield of 123b (450 mg) as a purple oil: ¹H NMR (300 MHz, CDCl₃) d7.17 (d, 1H, J=2.4 Hz), 5.55 (d, 1H, J=2.4 Hz), 3.43 (m, 1H), 2.92 (brs, 2H), 1.01 (m, 2H), 0.93 (m, 2H); MS (ESI+) m/z 124.1 (M+H).

Example 123c5-Bromo-3-(1-cyclopropyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one123c

A 250-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 123b(444 mg, 3.61 mmol), 2,5-dibromo-1-methylpyrazin-6-one (1.06 g, 3.97mmol), cesium carbonate (3.52 g, 10.8 mmol), and 1,4-dioxane (45 mL).After bubbling nitrogen through the resulting suspension for 30 min,Xantphos (177 mg, 0.306 mmol) andtris(dibenzylideneacetone)-dipalladium(0) (165 mg, 0.180 mmol) wereadded, and the reaction mixture was heated at reflux for 3 h. After thistime, the mixture was cooled to room temperature and diluted with ethylacetate (150 mL) and water (30 mL). The organic layer was separated, andthe aqueous layer was extracted with ethyl acetate (3×150 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The residue was triturated with methanol (20 mL)to afford a 63% yield (700 mg) of 123c as an off-white solid: mp161-163° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.00 (d, 1H,J=2.5 Hz), 7.57 (d, 1H, J=2.4 Hz), 7.38 (d, 1H, J=2.5 Hz), 6.05 (d, 1H,J=2.4 Hz), 3.61 (m, 1H), 3.49 (s, 1H), 0.95 (m, 4H); MS (ESI+) m/z 309.0(M+H).

A 150-mL single-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 123c(247 mg, 0.800 mmol), 111a (770 mg, 1.60 mmol), sodium carbonate (254mg, 2.40 mmol), DMF (5 mL), water (2.5 mL) and 1,4-dioxane (8 mL). Afterbubbling nitrogen through the resulting suspension for 30 min,tetrakis(triphenylphosphine)palladium(0) (93 mg, 0.080 mmol) was added,and the reaction mixture was heated at reflux for 14 h. After this time,the mixture was cooled to room temperature and diluted with ethylacetate (150 mL) and water (30 mL). The organic layer was separated, andthe aqueous layer was extracted with ethyl acetate (3×150 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The residue was dissolved in a mixture of THF (8mL), methanol (4 mL) and water (4 mL). To the resulting solution wasadded lithium hydroxide monohydrate (167 mg, 3.40 mmol). The mixture wasstirred for 2 h at room temperature and then concentrated in vacuo. Theresidue was partitioned between ethyl acetate (150 mL) and water (30mL). The organic layer was separated, and the aqueous layer wasextracted with a 20% (v/v) solution of methanol in methylene chloride(3×150 mL). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica, 0% to 10% methanol/methylene chloride) toafford a 19% yield (84 mg) of 123 as an off-white solid: mp 200-201° C.;¹H NMR (500 MHz, DMSO-d₆) δ 11.75 (s, 1H), 7.98 (s, 1H), 7.92 (s, 1H),7.418 (t, 1H, J=8.0 Hz), 7.31 (d, 1H, J=7.5 Hz), 7.27 (d, 1H, J=7.5 Hz),7.21 (s, 1H), 5.78 (s, 1H), 4.79 (m, 1H), 4.36 (m, 2H), 4.12 (m, 1H),3.80 (m, 1H), 3.56 (s, 3H), 2.95 (m, 1H), 2.80 (m, 1H), 2.78 (s, 2H),1.80 (m, 5H), 0.87 (m, 2H), 0.62 (m, 2H); MS (ESI+) m/z 542.1 (M+H).

Example 1245-[5-fluoro-2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-3-[(5-methyl-1H-pyrazol-3-yl)amino]-1,2-dihydropyridin-2-one124 Example 124a1-Methyl-3-(5-methyl-1H-pyrazol-3-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one124a

A microwave vial equipped with a magnetic stirrer was charged with5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridine-2(1H)-one112a (2.3 g, 8.3 mmol), (PinB)₂ (11 g, 41 mmol), Pd(dppf)Cl₂ (0.4 g, 0.5mmol), KOAc (2.4 g, 25 mmol), and 1,4-dioxane (150 mL). The system wasevacuated and then refilled with N₂. The reaction mixture was heated at100° C. for 0.5 h under microwave irradiation. Then, the mixture wascooled to room temperature and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified by flash columnchromatography eluting with 5:1 petroleum ether/ethyl acetate to afford124a (0.57 g, 21%). LCMS: [M+H]⁺ 331.

Example 124b4-Fluoro-2-(1-methyl-5-(5-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-benzylacetate 124b

A mixture of 124a (330 mg, 1 mmol),2-bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 197d (434 mg, 1 mmol), PdCl₂(dppf) (82 mg, 0.1 mmol), 2.0MNa₂CO₃ (2.0 equiv) in DME (10 mL) was heated at 120° C. under microwaveirradiation for 0.5 h. The solvent was evaporated in vacuo. The residuewas purified on reverse phase Combi-flash to give the title compound(160 mg, 29%). LCMS: [M+H]⁺ 559

A mixture of 124b (150 mg, 0.27 mmol) and LiOH (324 mg, 14 mmol) inisopropanol/THF (1:1, 10 mL) and water (3 mL) was stirred at 30° C. for2 h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (10 mL×2). The combined ethyl acetate extract wasconcentrated under reduced pressure and the residue was purified withprep-HPLC to give 124 (60 mg, 43%). LCMS: [M+H]⁺ 517. ¹H NMR (500 MHz,DMSO) δ 11.74 (s, 1H), 8.00 (m, 2H), 7.30 (m, 2H), 7.16 (dd, J=9.5, 1H),6.52 (s, 1H), 5.87 (s, 1H), 4.87 (m, 1H), 4.33 (m, 2H), 4.12 (m, 3H),3.87 (m, 1H), 3.56 (s, 3H), 2.59 (m, 2H), 2.47 (m, 2H), 2.45 (s, 3H),1.70 (m, 4H).

Example 1253-[(5-ethyl-1H-pyrazol-3-yl)amino]-5-[2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-1,2-dihydropyridin-2-one125 Experiment 125a5-Bromo-3-(5-ethyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one 125a

A 350-mL sealed tube equipped with a magnetic stirring bar was chargedwith 3,5-dibromo-1-methyl-1H-pyridin-2-one (3.2 g, 0.012 mol),5-ethyl-1H-pyrazol-3-amine (2.0 g, 0.018 mol), Pd₂(dba)₃ (0.55 g, 0.60mmol), 9,9-dimethyl-4,5-bis(diphenyl-phosphino)xanthene (0.49 g, 0.00084mol), Cs₂CO₃ (7.8 g, 0.024 mol), and 1,4-dioxane (80 mL). After thereaction mixture was stirred at 105° C. for 16 h, it was cooled to roomtemperature, partitioned between dichloromethane (50 mL) and water (30mL), and the organic phases were extracted with dichloromethane (30mL×3). The combined organic phases were washed with water (30 mL×2) andbrine (20 mL×1), dried (Na₂SO₄), and filtered through a pad of Celite,and the resulting filtrated was concentrated. To the crude product wereadded dichloromethane (20 mL) and ether (100 mL). The mixture wassonicated for 10 min., and the resulting precipitates were filtered togive 42% yield (1.5 g) of5-bromo-3-(5-ethyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one(125a) as a solid.

Example 125b2-(5-(5-Ethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 125b

In a 10-mL glass vessel equipped with a magnetic stirring bar wereplaced 125a (116 mg, 0.39 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (200 mg, 0.43 mmol), Pd(PPh₃)₄ (30 mg, 0.0.26 mmol) in 2 NNa₂CO₃ (2 mL) and 1,2-dimethoxyethane (5 mL). The vessel was sealed witha septum and placed into the microwave cavity. After the reactionmixture was stirred at 125° C. for 7 min., it was purified by flashchromatography (dichloromethane:methanol, 85:15) to give 23% (50 mg) of125b as a solid.

A 25-mL, single-necked, round-bottomed flask equipped with a magneticstirring bar was charged with 125b (50 mg, 0.090 mmol), LiOH.H₂O (20 mg,0.83 mmol), THF (2 mL), isopropanol (2 mL), and water (2 mL). After thereaction mixture was stirred at room temperature for 3 h, it waspartitioned between dichloromethane (5 mL) and water (5 mL), and theorganic phase was extracted with dichloromethane (5 mL×3). The combinedorganic phases were washed with water (5 mL×2) and brine (5 mL×1), dried(Na₂SO₄), and concentrated. The crude product was re-dissolved indichloromethane (3 mL). To this solution was added hexane (10 mL) andthe resulting precipitates were filtered to give 50% yield (23 mg) of2-(3-(5-(5-ethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one125 MS(ESI⁺) m/z 513.3 (M+H).

Example 1262-(2-(Hydroxymethyl)-3-(1-methyl-6-oxo-5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one126 Experiment 126a5-Bromo-1-methyl-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one126a

A 50 mL round bottom flask with a magnetic stirrer and reflux condenserwas charged with3-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one108d (250 mg, 0.7 mmol), aqueous NaOH (5N, 6 mL), ethanol (6 mL). Themixture stirred at reflux for 30 min. After this time, ethyl acetate (5mL) and water (5 mL) were added. The separated aqueous layer wasextracted with ethyl acetate (2×5 mL). The combined organics were washedwith brine (10 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure to afford a 91% yield (200 mg) of crude5-bromo-1-methyl-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one(126a).

Example 126b2-(1-Methyl-6-oxo-5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 126b

A microwave tube equipped with a magnetic stirrer was charged with 126a(210 mg, 0.65 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (330 mg, 0.7 mmol), DME (6 mL) and 1M aqueous sodiumcarbonate (1.9 mL). After bubbling N2 for 15 min, Pd(PPh₃)₄ (38 mg, 0.03mmol) was added. The mixture was heated in microwave to 135° C. for 15min. After this time, ethyl acetate (10 mL) and water (10 mL) wereadded. The separated aqueous layer was extracted with ethyl acetate(2×10 mL). The combined organics were washed with brine (20 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by column chromatography eluting witha gradient of CH₂Cl₂—9:1 CH₂Cl₂:MeOH to afford a 36% yield (140 mg) of126b.

A 25 mL round bottom flask with a magnetic stirrer was charged with 126b(140 mg, 0.24 mmol), lithium hydroxide (50 mg, 1.2 mmol), THF (1.2 mL),i-propanol (1.2 mL) and water (2.4 mL). The mixture stirred at rt for 1h. After this time ethyl acetate (5 mL) and water (5 mL) were added. Theseparated aqueous layer was extracted with ethyl acetate (2×5 mL). Thecombined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography eluting with a gradient ofCH₂Cl₂-60:35:5 CH₂Cl₂:Et₂O:MeOH to afford a 33% yield (42 mg) of 126. MS(ESI+) m/z 540.3 (M+H).

Example 1272-(5-fluoro-2-(hydroxymethyl)-3-(4-methyl-6-(4-morpholinophenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one127 Example 127a4-Fluoro-2-(4-methyl-6-(4-morpholinophenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 127a

A mixture of4-methyl-6-(4-morpholinophenylamino)-5-oxo-4,5-dihydropyrazin-2-ylboronic acid 122b (330 mg, 1 mmol),2-bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 197d (434 mg, 1 mmol), PdCl₂(dppf) (82 mg, 0.1 mmol), 2.0MNa₂CO₃ (1 mL, 2.0 equiv) in DME (10 mL) was heated at 130° C. undermicrowave irradiation for 0.5 h. The solvent was evaporated in vacuo andthe residue was purified on reverse phase Combi-flash to give 127a (200mg, 45%). LCMS: [M+H]⁺ 641.

A mixture of 127a (200 mg, 0.31 mmol) and LiOH (372 mg, 16 mmol) in^(i)PrOH/THF (1:1, 10 mL) and H₂O (3 mL) was stirred at 30° C. for 2 h.The mixture was then evaporated in vacuo and the residue was extractedwith ethyl acetate (10 mL×2). The combined extract was concentratedunder reduced pressure and the residue was purified with prep-HPLC togive 127 (58 mg, 33%). LCMS: [M+H]⁺ 599 ¹H NMR (500 MHz, DMSO) δ 9.13(s, 1H), 7.81 (m, 2H), 7.43 (s, 1H), 7.34 (m, 2H), 6.89 (m, 2H), 6.52(s, 1H), 4.85 (s, 1H), 4.14 (m, 1H), 3.72 (m, 3H), 3.56 (m, 3H), 3.07(m, 4H), 2.63 (m, 3H), 2.47 (m, 2H), 1.75 (m, 4H).

Example 1282-(3-(5-(5-(3-hydroxyazetidin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one128 Example 128a 1-(6-Nitropyridin-3-yl)azetidin-3-ol 128a

A 50 mL round bottom flask with a magnetic stirrer and reflux condenserwas charged with 3-hydroxyazetidine-HCl (2 g, 18.4 mmol),5-bromo-2-nitropyridine (2.1 g, 10.2 mmol), diisopropylethylamine (5.4mL, 30.7 mmol), tetrabutylammonium iodide (5.7 g, 15.4 mmol) andN,N-dimethylacetamide (10 mL). The mixture stirred at 120° C. for 16 h.After this time the mixture was cooled and ethyl acetate (25 mL) andwater (25 mL) were added. The separated aqueous layer was extracted withethyl acetate (2×10 mL). The combined organics were washed with brine(20 mL), dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by columnchromatography eluting with a gradient of 4:1 hexanes:ethyl acetatec—100 ethyl acetate to afford a 52% yield (1.9 g) of 128a.

Example 128b 1-(6-Aminopyridin-3-yl)azetidin-3-ol 128b

A 500-mL Parr hydrogenation bottle was charged with 128a (1.9 g, 9.6mmol), 10% palladium on carbon (50% wet, 570 mg dry weight) and ethanol(100 mL). The bottle was evacuated, charged with hydrogen gas to apressure of 50 psi and shaken for 24 h on a Parr hydrogenationapparatus. The catalyst was removed by filtration through a pad ofCelite 521 washing with 1:1 CH₂Cl₂:MeOH (500 mL). The resulting residuewas purified by column chromatography eluting with a gradient of 100%DCM—100% 3:1 DCM:MeOH to afford a 70% yield (1.1 g) of 128b.

Example 128c5-Bromo-3-(5-(3-hydroxyazetidin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one128c

A sealed tube was equipped with a magnetic stirrer and charged with 128b(375 mg, 2.3 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (848 g, 3.2mmol) and cesium carbonate (1.7 g, 5 mmol) in 1,4-dioxane (24 mL). Afterbubbling nitrogen through the solution for 30 min, Xantphos (160 mg, 0.3mmol) and tris(dibenzylideneacetone)dipalladium(0) (150 mg, 0.2 mmol)were added, and the reaction mixture was heated to 100° C. for 5 days.After this time, H₂O (20 mL) and EtOAc (20 mL) were added. The aqueouslayer was separated and extracted with ethyl acetate (2×20 mL). Thecombined organic extracts were washed with brine (50 mL) and dried oversodium sulfate. The resulting residue was purified by columnchromatography eluting with a gradient of CH₂Cl₂—9:1 CH₂Cl₂:MeOH toafford a 39% yield (430 mg) of 128c.

Example 128d2-(5-(5-(3-Hydroxyazetidin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 128d

A microwave tube equipped with a magnetic stirrer was charged with 128c(220 mg, 0.6 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (350 mg, 0.8 mmol), DME (7 mL) and 1M aqueous sodiumcarbonate (1.9 mL). After bubbling N2 for 15 min, Pd(PPh₃)₄ (36 mg, 0.03mmol) was added. The mixture was heated in microwave to 135° C. for 15min. After this time, ethyl acetate (10 mL) and water (10 mL) wereadded. The separated aqueous layer was extracted with ethyl acetate(2×10 mL). The combined organics were washed with brine (20 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by column chromatography eluting witha gradient of CH₂Cl₂—60:35:5 CH₂Cl₂:diethyl ether:MeOH to afford a 30%yield (110 mg) of 128d.

A 25 mL round bottom flask with a magnetic stirrer was charged with 128d(110 mg, 0.2 mmol), lithium hydroxide (38 mg, 0.9 mmol), THF (0.9 mL),i-propanol (0.9 mL) and water (1.8 mL). The mixture stirred at roomtemperature (rt) for 1 hr. After this time, ethyl acetate (5 mL) andwater (5 mL) were added. The separated aqueous layer was extracted withethyl acetate (2×5 mL). The combined organics were washed with brine (10mL), dried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by column chromatographyeluting with a gradient of CH₂Cl₂—60:35:5 CH₂Cl₂:diethyl ether:MeOH toafford a 12% yield (12 mg) of 128. MS (ESI+) m/z 567.2 (M+H).

Example 1292-(5-fluoro-2-(hydroxymethyl)-3-(4-methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one129 Example 129atert-Butyl-6-(6-(2-(acetoxymethyl)-5-fluoro-3-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate129a

A mixture of 482 mg of4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 210d and 435 mg oftert-butyl-6-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)-3,4-dihydro-isoquinoline-2(1H)-carboxylate120a, PdCl₂(dppf) (1110 mg, 0.015 mmol), 2 M Na₂CO₃ solution (3 mL) inDME (16 mL) was heated at 120° C. under microwave irradiation for 0.5 h.The solvent was evaporated in vacuo and the residue was purified onreverse phase Combi-flash to give 129a as a yellow solid (362 mg, 51%).MS: [M+H]⁺ 711.

Example 129b4-Fluoro-2-(4-methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 129b

To the solution of 129a (360 mg 0.51 mmol) in DCM (30 mL) was added 3MHCl in dioxane (8 mL) at room temperature. The mixture was stirred atroom temperature for 5 h. After the reaction was completed, the solventwas removed at reduced pressure to afford 129b as a yellow solid (310mg, 99%).

Following Example 149, 250 mg of 129b was converted to 129 as a whitesolid (98 mg, 42%). ¹H NMR (500 MHz, MeOD) δ 7.62 (s, 1H), 7.55 (dd,J=7.0, 1H), 7.41 (dd, J=9.5, 1H), 7.38 (s, 1H), 7.20 (dd, J=9.5, 1H),7.04 (d, J=8.5, 1H), 6.71 (s, 1H), 4.59 (d, J=12, 1H), 4.8 (d, J=11.5,1H), 4.20 (m, 3H), 4.00 (m, 3H), 3.64 (s, 3H), 3.13 (m, 2H), 2.86 (m,2H), 2.64 (m, 2H), 2.54 (m, 2H), 1.88 (m, 2H), 1.78 (m, 2H).

Example 1302-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one130 Example 130a5-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-nitropyridine 130a

To a round-bottomed flask equipped with a stirring bar,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(1.50 g, 6.72 mmol), 5-bromo-2-nitropyridine (1.64 g, 8.07 mmol),Pd(PPh₃)₄ (388 mg, 0.336 mmol), Na₂CO₃ aqueous solution (1.0 N, 20.2 mL,20.2 mmol), dioxane (60.6 mL) were added. The reaction mixture washeated at 100° C. for 10 hrs. CH₂Cl₂ (200 mL) was added to the resultingmixture was washed with water (30 mL×3). CH₂Cl₂ (200 mL) was added andthe resulting mixture was washed with water (30 mL×3), brine (30 mL×1),dried over MgSO₄, filtered, and removed solvent in vacuo. Silica gelcolumn chromatography (MeOH:DCM=5:95) gave5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-nitropyridine (130a) as ayellow solid.

Example 130b 5-(1-Methylpiperidin-4-yl)pyridin-2-amine 130b

In a hydrogenation bottle, 130a (1.25 g, 5.73 mmol), EtOH (100 mL), 10%Pd/C (304 mmol, 0.286 mmol) were added. The mixture was hydrogenated at55 psi for 2 hrs, filtered through celite, and washed with MeOH (20 mL).The solvent was removed in vacuo and off-white solids were obtained as5-(1-methylpiperidin-4-yl)pyridin-2-amine 130b (1.13 g, 100%).

Example 130c5-Bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one130c

To a round-bottomed flask equipped with a stirring bar, 130b (1.08 g,5.65 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.26 g, 8.47 mmol),Pd₂(dba)₃ (517 mg, 0.565 mmol), XantPhos (523 mg, 0.903 mmol), Cs₂CO₃(6.07 g, 18.6 mmol) and dioxane (28.3 mL) were added. The reactionmixture was heated at 100° C. overnight. CH₂Cl₂ (200 mL) was added tothe resulting mixture was washed with water (30 mL×3). CH₂Cl₂ (200 mL)was added and the resulting mixture was washed with water (30 mL×3),brine (30 mL×1), dried over MgSO₄, filtered, and removed solvent invacuo. CH₂Cl₂/ether (1:2, 5 mL) were added followed by sonication, theprecipitation was filtered and dried. Compound 130c was obtained as agreen solid, 784 mg (37%).

Example 130d2-(1-Methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 130d

To a microwave tube equipped with a stirring bar, 130c (250 mg, 0.663mmol),2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one114a (338 mg, 0.729 mmol), Pd(PPh₃)₄ (38.3 mg, 0.033 mmol), Na₂CO₃aqueous solution (1.0 N, 2.19 mL, 2.19 mmol), DME (2 mL) were added. Themixture was reacted in microwave at 135° C. for 15 min. CH₂Cl₂ (200 mL)was added and the resulting mixture was washed with water (30 mL×3),brine (30 mL×1), dried over MgSO₄, filtered, and removed solvent invacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 130d.

To a round-bottomed flask equipped with a stirring bar, 130d THF (1.25mL), i-PrOH (1.25 mL), H₂O (1.25 mL), LiOH H₂O (135 mg) were added. Theresulting mixture was stirred at RT for 1 hr. The solvent was removed invacuo and the resulting residue was added to CH₂Cl₂ (200 mL), thesolution was washed with water (30 mL×3), brine (30 mL×1), dried overMgSO₄, filtered, and removed solvent in vacuo. Silica gel columnchromatography (MeOH: CH₂Cl₂=10:90) gave 130 as an off-white solid, 39mg. MS (ESI+) m/z 593.4 (M+H).

Example 1315-(3-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-2-(hydroxymethyl)phenyl)-1-methyl-3-(1-ethyl-1H-pyrazol-4-ylamino)pyrazin-2(1H)-one 131 Example 131a2-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylAcetate 131a

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 105i (411 mg, 0.917 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (698 mg, 2.75mmol), potassium acetate (360 mg, 3.66 mmol) and 1,4-dioxane (15 mL).After bubbling nitrogen through the resulting suspension for 30 min,Pd(dppf)Cl₂.CH₂Cl₂ (35 mg, 0.047 mmol) was added. A reflux condenser wasattached to the flask, and the reaction mixture was heated at 90° C. for14 h. After this time, more Pd(dppf)Cl₂.CH₂Cl₂ (70 mg, 0.094 mmol) wasadded, and the reaction was stirred for 4 h at 90° C. After this time,the mixture was diluted with ethyl acetate (100 mL) and water (75 mL),and the layers were separated. The aqueous layer was extracted withethyl acetate (50 mL), and the combined organic layers were washed withbrine (50 mL) and dried over sodium sulfate. The drying agent wasremoved by filtration. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by flash columnchromatography (silica, 70:30 hexanes/ethyl acetate) to afford 131a in82% yield (373 mg) as an amorphous off-white solid: ¹H NMR (500 MHz,CDCl₃) d 7.81 (dd, J=7.5, 1.5 Hz, 1H), 7.41 (t, J=7.5 Hz, 1H), 7.35 (dd,J=7.0, 1.5 Hz, 1H), 5.51 (d, J=11.5 Hz, 1H), 5.26 (d, J=11.5 Hz, 1H),4.03-3.98 (m, 1H), 3.77-3.72 (m, 1H), 3.05-2.98 (m, 1H), 2.82-2.76 (m,1H), 2.76 (s, 2H), 2.52 (s, 2H), 1.99 (s, 3H), 1.33 (s, 12H), 1.27 (s,3H), 1.26 (s, 3H); MS (ESI+) m/z 496.2 (M+H).

Example 131b5-Bromo-3-(1-ethyl-1H-pyrazol-4-ylamino)-1-methylpyrazin-2(1H)-one 131b

Following Example 111b, reaction of 1-ethyl-1H-pyrazol-4-amine (500 mg,4.50 mmol) and 3,5-dibromo-1-methyl pyrazin-2(1H)-one (1.33 g, 4.95mmol) afforded a 75% yield (1.01 g) of 131b as an off-white solid: mp237-239° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.90 (s, 1H), 8.02 (s, 1H),7.73 (s, 1H), 7.20 (s, 1H), 4.11 (q, 2H, J=7.5 Hz), 3.41 (s, 3H), 1.34(t, 3H, J=7.3 Hz); MS (ESI+) m/z 298.0 (M+H).

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 131b (200 mg, 0.670 mmol),boronate 131a (365 mg, 0.737 mmol), sodium carbonate (184 mg, 1.73mmol), DMF (2 mL), water (2 mL) and 1,4-dioxane (10 mL). After bubblingnitrogen through the resulting suspension for 30 min,tetrakis(triphenylphosphine)palladium(0) (134 mg, 0.116 mmol) was added.A reflux condenser was attached to the flask, and the reaction mixturewas heated at 100° C. for 14 h. After this time, the mixture was dilutedwith 90:10 methylene chloride/methanol (100 mL) and water (75 mL), andthe layers were separated. The aqueous layer was extracted with 90:10methylene chloride/methanol (2×50 mL), and the combined organic layerswere washed with brine (100 mL) and dried over sodium sulfate. Thedrying agent was removed by filtration. The filtrate was concentratedunder reduced pressure, and the resulting residue was dissolved in amixture of THF (5 mL), water (5 mL) and methanol (5 mL). Lithiumhydroxide monohydrate (121 mg, 2.89 mmol) was added, and the mixture wasstirred at room temperature for 2 h. After this time, the mixture wasdiluted with 90:10 methylene chloride/methanol (100 mL) and water (50mL), and the layers were separated. The aqueous layer was extracted with90:10 methylene chloride/methanol (2×75 mL), and the combined organiclayers were washed with brine (100 mL) and dried over sodium sulfate.The drying agent was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by flash column chromatography (silica, 90:10 methylenechloride/methanol) to afford 131 in 26% yield (96 mg) as an amorphousyellow solid: mp 138-140° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.56 (s, 1H),8.16 (s, 1H), 7.73 (s, 1H), 7.56 (dd, J=7.5, 1.0 Hz, 1H), 7.46 (t, J=8.0Hz, 1H), 7.34 (dd, J=7.5, 1.0 Hz, 1H), 7.31 (s, 1H), 4.85-4.82 (m, 1H),4.56-4.53 (m, 1H), 4.47-4.44 (m, 1H), 4.08-4.02 (m, 3H), 3.90-3.86 (m,1H), 3.52 (s, 3H), 3.03-3.00 (m, 1H), 2.92-2.87 (m, 1H), 2.75 (s, 2H),2.54 (d, J=5.0 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H), 1.23 (s, 6H); MS (ESI+)m/z 545.1 (M+H).

Example 1322-(2-(hydroxymethyl)-3-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one132 Example 132a2-(2-(Acetydroxymethyl)-3-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one132a

Following Example 119d, 119c (150 mg, 0.50 mmol), 113a (257 mg, 0.55mmol), 1N Na₂CO₃ (1.1 mL) and tetrakis(tripheny-phosphine)-palladium(0)(29 mg, 5 mol %) were reacted to give 132a (160 mg, 53% yield).

Following Example 132, 132a (160 mg, 0.27 mmol), 1N LiOH (1.3 mL), THF(2 mL) and isopropanol (2 mL) were reacted to give 132 (118 mg, 78%yield) as a white solid. MS (ESI+) m/z 558.3 (M+H).

Example 1332-(2-(Hydroxymethyl)-3-(6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-1(2H)-one133 Example 133a 6-Chloro-4-(pyrimidin-4-ylamino)pyridazin-3(2H)-one133a

A 1-L three-neck round-bottomed flask equipped with a mechanicalstirrer, nitrogen inlet and reflux condenser was charged with4-bromo-6-chloropyridazin-3(2H)-one (7.30 g, 35.0 mmol),2-aminopyrimidine (3.33 g, 35.0 mmol), cesium carbonate (25.0 g, 76.8mmol) and 1,4-dioxane (345 mL). After bubbling nitrogen through theresulting solution for 30 minutes, Xantphos (1.71 g, 2.96 mmol) andtris(dibenzylideneacetone)di-palladium(0) (1.60 g, 1.74 mmol) were addedand the reaction mixture was heated at reflux for 3 h. After this timethe reaction was cooled to room temperature and filtered. The filtercake was washed with methylene chloride (3×50 mL) and water (3×20 mL)and dried in a vacuum oven overnight at 45° C. to afford 133a (5.54 g,71%) as a tan solid: mp>300° C.; ¹H NMR (500 MHz, DMSO-d₆) d 13.28 (brs, 1H), 9.90 (br s, 1H), 8.91 (s, 1H), 8.51 (d, 1H, J=6.0 Hz), 8.39 (s,1H), 7.53 (dd, 1H, J=1.5, 6.0 Hz); MS (ESI+) m/z 224.1 (M+H).

Following Example 119d, 133a (145 mg, 0.650 mmol) and 111a (313 mg,0.650 mmol) afforded a 18% yield (60 mg) of 133 as a pink solid: mp150-151° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 13.30 (s, 1H), 9.81 (s, 1H),8.79 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 7.48 (m, 2H), 7.43 (m, 2H),4.66 (m, 1H), 4.44 (m, 1H), 4.38 (m, 1H), 4.04 (m, 1H), 3.85 (m, 1H),2.94 (m, 1H), 2.87 (m, 1H), 2.77 (m, 2H), 2.53 (m, 1H), 1.79 (m, 4H); MS(ESI+) m/z 501.1 (M+H).

Example 1342-(2-(Hydroxymethyl)-3-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one134 Example 134a Methyl3-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-1-methyl-1H-pyrazole-5-carboxylate134a

Following Example 119a, 3,5-dibromo-1-methylpyridin-2(1H)-one (2.0 g,7.5 mmol) was converted to 134a.

Example 134b5-Bromo-3-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one134b

Following Example 119b, 132a (330 mg, 0.97 mmol) and 3.0M in etherMeMgBr (5.8 mmol, 1.9 mL) in THF (10 mL) were reacted to give 134b (270mg, 82% yield).

Example 134c2-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 134c

Following Example 119, 113b (120 mg, 0.35 mmol), 113a (180 mg, 0.39mmol), 1N Na₂CO₃ (0.8 mL) and Palladium tetrakis (20 mg, 5 mol %) werereacted to give 134c (85 mg, 40% yield).

Following Example 119, 134c (80 mg, 0.13 mmol), 1N LiOH (0.7 mL), THF(1.5 mL) and isopropanol (1.5 mL) were reacted. The product was purifiedvia column chromatography, silica, MeOH/CH2Cl2 then triturated withEtOAc to give 134 (18 mg, 25% yield). MS (ESI+) m/z 557.3 (M+H).

Example 1352-(3-(5-(5-cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one135 Example 135a5-Cyclopropyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 135a

A mixture of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 101c(4 g, 12.9 mmol) and cyclopropanamine (7.35 g, 129 mmol) in THF (40 mL)was stirred at 30° C. overnight. After the completion of the reaction,the mixture was filtered off and the solid was washed with THF (100 mL).The filtrate was concentrated under reduced pressure to give 135a (2.68g, 99%). MS: [M+H]⁺ 209.

Example 135b5-Cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 135b

A mixture of5-cyclopropyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 135a(2.68 g, 12.9 mmol), Fe (3.6 g, 64.4 mmol) and NH₄Cl (4.1 g, 77.4 mmol)in ethanol (30 mL) and water (5 mL) was heated at reflux for 2 h. Afterthe completion of the reaction, the mixture was filtered off. And thesolid was washed with ethanol (150 mL). The filtrate was evaporated invacuo and the residue was extracted with methanol/methylene chloride(1/7). The combined extracts were dried over Na₂SO₄ and evaporated. Theresidue was purified on reverse phase Combi-flash to give 135b (1.8 g,75%). MS: [M+H]⁺ 179.

Example 135c5-Bromo-3-(5-cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methylpyridin-2(1H)-one135c

A mixture of5-cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 135b(1.39 g, 7.8 mmol), XantPhos (450 mg, 0.78 mmol), Pd₂dba₃ (476 mg, 0.52mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.72 g, 6.5 mmol) andCs₂CO₃ (6.3 mg. 19.5 mmol) in 1,4-dioxane (30 mL) was heated at refluxfor 1 h. After the completion of the reaction the mixture was filteredoff and the solid was washed with methanol (60 mL). The filtrate wasevaporated in vacuo and the residue was purified on reverse phaseCombi-flash to give 135c (0.84 g, 30%). MS: [M+H]⁺ 364.

Example 135d2-(5-(5-Cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 135d

A mixture of4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (105 mg, 0.26 mmol), 135c (100 mg, 0.28 mmol), PdCl₂(dppf)(29 mg, 0.039 mmol), K₃PO₄ (100 mg), and NaOAc (50 mg) in MeCN (10 mL)and water (3 mL) was heated at 110° C. for 2 h. The solvent wasevaporated in vacuo. The residue was purified on reverse phaseCombi-flash to give 135d (100 mg, 60%). MS: [M+H]⁺ 640.

A mixture of 135d (100 mg, 0.16 mmol) and LiOH hydrate (100 mg. 2.3mmol) in isopropanol (10 mL) and water (3 mL) was stirred at 30° C. for2 h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (10 mL×2). The combined extracts were concentratedunder reduced pressure and the residue was purified with prep-HPLC togive 135 (40 mg, 42%). MS: [M+H]⁺ 598. ¹H NMR (500 MHz, MeOD) δ 7.89 (s,1H), 7.26 (s, 1H), 7.20 (d, J=9.0, 2H), 6.72 (s, 1H), 5.88 (s, 1H),4.52-4.44 (m, 2H), 4.22-4.18 (m, 3H), 4.03-3.97 (m, 3H), 3.81 (s, 2H),3.69 (s, 3H), 3.15-3.13 (m, 2H), 2.67-2.61 (m, 2H), 2.57-2.51 (m, 2H),1.96-1.87 (m, 3H), 1.81-1.75 (m, 2H), 0.62-0.58 (m, 2H), 0.53-0.49 (m,2H).

Example 1365-(3-{5-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-5-fluoro-2-(hydroxymethyl)phenyl)-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one136 Example 136a 3-Cyclopropyl-3-oxopropanenitrile 136a

To a solution of CH₃CN (0.34 mL, 6.58 mmol) in THF (3 mL) at −78° C.under N₂ protection was added LDA (3.3 mL, 6.58 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 3 h. Then ethylcyclopropanecarboxylate (0.5 g, 4.38 mmol) in THF (2 mL) was added andthe mixture was allowed to warm to room temperature in a period of 1 h.Water (2 mL) was added and the solvents were removed under reducedpressure. CH₂Cl₂ (2 mL) was added and the pH of the mixture was adjustedto 5 with 2N HCl. It was then extracted with CH₂Cl₂ (5 mL×2), dried overNa₂SO₄, and concentrated to afford 136a as a yellow oil, which was usedin the next step without further purification.

Example 136b 3-Cyclopropyl-1H-pyrazol-5-amine 136b

To a solution of 136a (477 mg, 4.38 mmol) in MeOH (5 mL) was addedN₂H₄.H₂O (80%) (5 mL). The reaction mixture was heated at 75° C. for 15h. MeOH was removed under reduced pressure. The residue was extractedwith CH₂Cl₂ (2×8 mL), dried over Na₂SO₄, and concentrated. The residuewas purified by flash column eluting with 100:1 CH₂Cl₂/MeOH to afford136b as a yellow oil (37%, for two steps). LCMS: (M+H)⁺ 124.

Example 136c tert-Butyl 5-Amino-3-cyclopropyl-1H-pyrazole-1-carboxylate136c

To a mixture of 136b (0.25 g, 2 mmol) and K₂CO₃ (0.828 g, 6 mmol) in THF(5 mL) was added (Boc)₂O (0.436 g, 2 mmol) in THF (5 mL). The reactionmixture was stirred at room temperature for 15 h. It was then filteredand concentrated. The residue was purified by flash column eluting with6:1 petroleum ether/ethyl acetate to afford 136c as a white solid (240mg, 54%). LCMS: (M-Boc)⁺ 124.

Example 136d5-Bromo-3-(3-cyclopropyl-1H-pyrazol-5-ylamino)-1-methylpyridin-2(1H)-one136d

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 136c(455 mg, 1.95 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (0.40 g, 1.5mmol) and cesium carbonate (1.22 g, 3.75 mmol). After bubbling nitrogenthrough the resulting mixture for 30 minutes, XantPhos (87 mg, 0.15mmol) and tris(dibenzylideneacetone)dipalladium(0) (70 mg, 0.075 mmol)were added, and the reaction mixture was heated at reflux for 15 h.After this time the reaction was cooled to room temperature, partitionedbetween ethyl acetate (30 mL) and water (30 mL) and filtered. Theaqueous layer was separated and extracted with ethyl acetate 2×50 mL).The organic layers were combined, washed with brine (50 mL) and driedover Na₂SO₄. The drying agent was removed by filtration and the filtratewas concentrated under reduced pressure. The residue was purified onflash column eluting with 50:1 CH₂Cl₂/MeOH to afford 136d as a yellowsolid (320 mg, 50%). LCMS: (M+H)⁺ 309. ¹H NMR (500 MHz, DMSO) δ 11.85(s, 1H), 8.23 (s, 1H), 8.02 (d, J=2.5, 1H), 7.35 (d, J=2.5, 1H), 5.77(d, J=2, 1H), 3.46 (s, 3H), 1.83 (m, 1H), 0.90 (m, 2H), 0.64 (m, 2H)

Example 136e(2-{5-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-1-methyl-6-oxopyridin-3-yl}-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl)methylacetate 136e

A 25 mL sealed vial was charged with(4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methylacetate 212b (580 mg, 1.16 mmol), 136d (300 mg, 0.97 mmol), CH₃COONa(160 mg, 1.94 mmol), K₃PO₄ (410 mg, 1.94 mmol), PdCl₂(dppf) (100 mg,0.12 mmol), CH₃CN (12 mL), and H₂O (1 mL). The mixture was heated at110° C. for 2 hours. The reaction mixture was evaporated and the residuewas purified by flash column eluting with 50:1 methylenechloride/methanol containing 0.5% triethylamine to give 136e as a blacksolid (300 mg, 52%).

To a solution of 136e (300 mg, 0.50 mmol) in propan-2-ol (3 mL),tetrahydrofuran (3 mL), and water (3 mL) was added LiOH (1.0 g, 25mmol). The mixture was stirred at 30° C. for 2 h. Then, 20 mL H₂O wasadded and extracted with EA (30 mL×3). The combined organic layer wasdried with Na₂SO₄ and concentrated to give yellow solid, which wasfurther purified by prep-HPLC to give 136 as a white solid (200 mg,70%). LCMS: (M+H)⁺ 560 ¹H NMR (500 MHz, DMSO) δ 7.78 (s, 1H), 7.25 (d,J=2.5, 1H), 7.21 (m, 2H), 5.79 (s, 1H), 4.48 (m, 2H), 4.15 (m, 1H), 4.00(m, 1H), 3.69 (s, 3H), 3.07 (m, 1H), 2.95 (m, 1H), 2.85 (m, 2H), 2.61(m, 2H), 1.89 (m, 5H), 0.96 (m, 2H), 0.73 (m, 2H).

Example 1375-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxopyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one137 Example 137a5-[5-Fluoro-3-[1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrazin-2-ylamino)-6-oxopyridin-3-yl]benzylacetate]-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one137a

A 25 mL sealed tube was charged with(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 212b (990 mg, 2 mmol),5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one252a (500 mg, 1.3 mmol), CH₃COONa (220 mg, 2.6 mmol), K₃PO₄ (700 mg, 2.6mmol), and PdCl₂(dppf) (110 mg, 0.13 mmol) suspended in CH₃CN (25 mL)and H₂O (1 mL). The mixture was stirred at 110° C. for 2 hours. Thesolvent was then evaporated and the residue was purified by silical-gelcolumn eluting with 20:1 CH₂Cl₂/methanol to give 137a as a brown solid(300 mg, 35%). MS: (M+H)⁺ 673.

To a solution of 137a (270 mg, 0.4 mmol) in propan-2-ol (8 mL),tetrahydrofuran (8 mL), and water (1.5 mL) was added LiOH (964 mg, 40mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedunder reduced pressure and the residue was purified by prep-HPLC toafford 137 as a yellow solid (84 mg, 33%). MS: (M+H)⁺ 631. 1H NMR (500MHz, MeOD) δ 1.87 (s, 4H), 2.52-2.56 (d, 2H), 2.83-2.90 (d, 5H), 3.01(s, 1H), 3.56-3.74 (t, 6H), 3.96-4.01 (t, 4H), 4.44-4.48 (t, 2H), 4.63(s, 2H), 4.74 (s, 2H), 5.87 (s, 1H), 7.16-7.18 (d, 2H), 7.25 (s, 1H),7.89 (s, 1H).

Example 1382-(3-(5-(5-(4-Ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one138 Example 138a 1-Ethyl-4-(6-nitropyridin-3-yl)piperazine 138a

To a sealed tube equipped with a stirring bar, 5-bromo-2-nitropyridine(3.00 g, 14.78 mmol), 1-ethylpiperazine (5.06 g, 44.34 mmol),tetrabutylammonium iodide (273 mmol, 0.739 mmol), K₂CO₃ (6.128 g, 44.34mmol), and DMSO (30 mL) were added. The tube was sealed and heated at90° C. overnight. Water (200 mL) was added and the precipitation wasfiltered to afford 138a as a yellow solid, 1.24 g.

Example 138b 5-(4-Ethylpiperazin-1-yl)pyridin-2-amine 138b

In a hydrogenation bottle, 138a (2.59 g, 10.96 mmol), EtOH (100 mL), 10%Pd/C (580 mg, 0.55 mmol) were added. The mixture was hydrogenated at 55psi for 2 hrs, and then filtered through celite and washed with MeOH (20mL). The solvent was removed in vacuo and pink solids were obtained as138b (2.51 g, 82%).

Example 138c5-Bromo-3-(5-(4-Ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one138c

To a round-bottomed flask equipped with a stirring bar, 138b (2.52 g,12.22 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (4.89 g, 18.32 mmol),Pd₂(dba)₃ (1.12 g, 1.22 mmol), XantPhos (1.13 mg, 1.96 mmol), Cs₂CO₃(13.14 g, 40.33 mmol) and dioxane (50 mL) were added. The reactionmixture was heated at 100° C. overnight. CH₂Cl₂ (200 mL) was added tothe resulting mixture was washed with water (30 mL×3). CH₂Cl₂ (200 mL)was added and the resulting mixture was washed with water (30 mL×3),brine (30 mL×1), dried over MgSO₄, filtered, and removed solvent invacuo. CH₂Cl₂/ether (1:2, 5 mL) was added followed by sonication, theprecipitation was filtered as 138c, a yellow solid, 2.718 g (57%).

Example 138d2-(5-(5-(4-Ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 138d

To a microwave tube equipped with a stirring bar, 138c (250 mg, 0.637mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (325.5 mg, 0.701 mmol), Pd(PPh₃)₄ (36.8 mg, 0.0319 mmol),Na₂CO₃ aqueous solution (1.0 N, 2.10 mL, 2.10 mmol), DME (2.0 mL) wereadded. The mixture was reacted in microwave at 135° C. for 15 min.CH₂Cl₂ (200 mL) was added and the resulting mixture was washed withwater (30 mL×3), brine (30 mL×1), dried over MgSO₄, filtered, andremoved solvent in vacuo. Silica gel column chromatography (MeOH:CH₂Cl₂=5:95) gave2-(5-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 138d.

To a round-bottomed flask equipped with a stirring bar, 138d, THF (5.0mL), i-PrOH (5.0 mL), H₂O (5.0 mL), LiOH H₂O (200 mg) were added. Theresulting mixture was stirred at RT for 2 hrs. Removed all the solventin vacuo and the resulting residue was added to CH₂Cl₂ (200 mL), thesolution was washed with water (30 mL×3), brine (30 mL×1), dried overMgSO₄, filtered, and removed solvent in vacuo. Silica gel columnchromatography (MeOH: CH₂Cl₂=10:90) gave 138 as a gray solid, 60 mg. MS(ESI+) m/z 608.3 (M+H).

Example 1393-{[4-(3-Hydroxy-3-methylazetidin-1-yl)phenyl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-1,2-dihydropyrazin-2-one139

Following Example 301, 1-(4-aminophenyl)-3-methylazetidin-3-ol wasconverted to 99 mg of 139 as a white solid. MS (ESI+) m/z 581 (M+H).

Example 1402-(3-(6-(1-(2-Hydroxyethyl)-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one140 Example 140a5-Bromo-3-(1-(2-hydroxyethyl)-1H-pyrazol-4-ylamino)-1-methylpyrazin-2(1H)-one140a

A flask equipped with a magnetic stirrer was charged with1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-4-amine 116b (1.7 g,7.1 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.25 g, 4.7 mmol), andIPA (25 mL). The system was evacuated and then refilled with N₂. Thereaction mixture was heated at 90° C. for 6 h. Then, the mixture wascooled to room temperature and concentrated under reduced pressure. Theresidue was purified by flash column chromatography eluting withpetroleum ether/ethyl acetate to afford 140a (1.7 g, 78%). LCMS: [M+H]⁺314.

Example 140b2-(6-(1-(2-Hydroxyethyl)-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 140b

A mixture of 140a (595 mg, 1.9 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (882 mg, 1.9 mmol), CH₃COONa (309 mg, 3.8 mmol),PdCl₂(dppf) (153 mg, 0.19 mmol) and K₃PO₄ (1 g, 3.8 mmol) suspended inCH₃CN (30 mL) and H₂O (2 mL) was heated at 110° C. for 15 h under argonatmosphere. After reaction CH₃CN was evaporated and the residue waspurified by reverse phase Combi-flash eluting with 0.3% NH₄HCO₃ in 1:4water/CH₃CN to give 140b as a brown solid (477 mg, 44%). LCMS: [M+H]⁺572.

A mixture of 140b (410 mg, 0.72 mmol) and LiOH (372 mg, 16 mmol) in^(i)PrOH/THF (1:1, 10 mL) and H₂O (3 mL) was stirred at 30° C. for 2 h.The mixture was evaporated in vacuo and the residue was extracted withEtOAc (10 mL×2). The combined extract was concentrated under reducedpressure and the residue was purified on pre-HPLC to give 140 (200 mg,54%). LCMS: [M+H]⁺ 530 ¹H NMR (500 MHz, CDCl3) δ 7.71 (s, 1H), 7.68 (s,1H), 7.49 (s, 1H), 7.36 (m, 2H), 7.27 (m, 1H), 6.92 (s, 1H), 6.78 (s,1H), 5.29 (s, 1H), 4.43 (d, J=12, 1H), 4.21 (m, 4H), 4.04 (m, 2H), 4.01(m, 3H), 3.63 (s, 3H), 2.55 (dt, J=14.5, 4H), 1.78 (m, 4H).

Example 1412-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one141 Example 141a5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine 141a

A solution of 1-methyl-4-piperidone (11.3 g, 100 mmol) in 2-propanol (80mL) was heated to 50° C. To the solution was sequentially added asolution of cyanamide (4.2 g, 100 mmol) in 2-propanol (25 mL) and sulfurpowder (3.2 g). After a catalytic amount of pyrrolidine (1.3 mL) wasadded thereto, the resultant mixture was stirred at or above 50° C. for2 hours. The reaction mixture was allowed to cool to room temperature,followed by stirring for overnight. The resultant mixture was cooled toor below 10° C. in an ice-water bath, and was stirred for 1 hour at thesame temperature. The precipitated crystals were collected byfiltration, and washed with 2-propanol (20 mL). The wet crystals weredried under reduced pressure, to give 141a (10 g, 60%). LCMS: [M+H]⁺ 170¹H NMR (500 MHz, DMSO) δ 6.70 (s, 2H), 3.31 (s, 2H), 2.61 (t, J=5.5,2H), 2.45 (m, 2H), 2.33 (s, 3H).

Example 141b5-Bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-ylamino)pyridin-2(1H)-one141b

Following Example 110c, 3 g of 141a and 4 g of3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 141b as ayellow solid (2.8 g, 52%). LCMS: [M+H]⁺ 357

Example 141c2-(1-Methyl-5-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 141c

Following Example 147b, 232 mg of 114a and 178 mg of 141b were reactedto give 141c as a yellow solid (240 mg, 80%). LCMS: [M+H]⁺ 613

Following Example 148, 240 mg of 141c was converted to 141 as a whitesolid (112 mg, 50%). LCMS: [M+H]⁺ 571.

Example 1422-(3-(5-(1,5-Dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one142 Example 142a5-Bromo-3-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one142a

A solution of5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 112a(2.8 g, 9.9 mmol) in anhydrous DMF (10 mL) was treated with 60%dispersion of NaH in mineral oil (0.5 g, 13 mmol) while stirring undernitrogen. After effervescence the reaction was stirred for an additional30 minutes. At this time the reaction was treated with MeI (0.98 g, 7mmol) and continued to stir under nitrogen for 2 hours. Water (50 mL)was added slowly and the mixture was filtered and then concentrated. Theresidue was purified by flash column chromatography eluting withpetroleum ether/ethyl acetate to afford 142a (0.7 g, 24%), which wasused directly without further purification. LCMS: (M+H)+297.

Example 142b2-(5-(1,5-Dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 142b

A mixture of 142a (510 mg, 1.7 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (882 mg, 1.9 mmol), CH₃COONa (309 mg, 3.8 mmol),PdCl₂(dppf) (153 mg, 0.19 mmol), and K₃PO₄ (1 g, 3.8 mmol) suspended inCH₃CN (30 mL) and H₂O (2 mL) was heated at 110° C. for 15 h under argonatmosphere. It was then evaporated and the residue was purified byreverse phase Combi-flash eluting with 0.3% NH₄HCO₃ 1:4 water/CH₃CN togive 142b as a brown solid (200 mg, 21%). LCMS: [M+H]⁺ 555.

A mixture of 142b (210 mg, 0.38 mmol) and LiOH (372 mg, 16 mmol) in^(i)PrOH/THF (1:1, 10 mL) and water (3 mL) was stirred at 30° C. for 2h. The mixture was evaporated in vacuo, and the residue was extractedwith EtOAc (10 mL×2). The combined extract was concentrated underreduced pressure and the residue was purified on prep-HPLC to give 142(95 mg, 50%). LCMS: [M+H]⁺ 513. ¹H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H),7.43 (m, 2H), 7.38 (s, 1H), 7.30 (m, 1H), 7.21 (m, 1H), 6.84 (s, 1H),5.71 (s, 1H), 4.58 (d, J=11.5, 1H), 4.38 (d, J=11.5, 1H), 4.13 (m, 3H),3.94 (m, 1H), 3.67 (s, 3H), 3.64 (s, 3H), 2.57 (m, 4H), 2.21 (s, 3H),1.78 (m, 4H).

Example 1432-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one143 Example 143a1-Methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-ylboronicacid 143a

To a solution of5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one252a (1 g, 2.64 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2 g, 7.92mmol) in dioxane (40 mL) was added PdCl₂(dppf) (215 mg, 0.26 mmol) andCH₃COOK (776 mg, 7.92 mmol). The mixture was stirred at 100° C. for 6 hunder argon atmosphere. After reaction the mixture was filtered andevaporated in vacuo. The residue was purified by reverse phasecombiflash eluting with 0.3% NH₄HCO₃ in 1:3 water/CH₃CN to give 143a asa white solid (300 mg, 33%). MS: (M+H)⁺ 346.

Example 143b4-Fluoro-2-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 143b

A 25 mL vial was charged with 143a (238 mg, 0.7 mmol),2-bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 197d (300 mg, 0.7 mmol), Na₂CO₃ (147 mg, 1.4 mmol), PdCl₂(dppf)(56 mg, 0.07 mmol) suspended in DME (15 mL), and H₂O (1 mL). Theresulting orange mixture was heated for 30 minutes in a Biotagemicrowave reactor at 130° C. After reaction the residue was purified byreverse phase Combi-flash eluting with 0.3% NH₄HCO₃ in 1:7 water/CH₃CNto give 143b as a brown solid (150 mg, 33%). MS: (M+H)⁺ 656.

To a solution of4-fluoro-2-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 143b (120 mg, 0.18 mmol) in propan-2-ol (5 mL), tetrahydrofuran(5 mL) and water (1.5 mL) was added LiOH (440 mg, 18 mmol). The mixturewas stirred at 30° C. for 2 h. The reaction mixture was then evaporatedand the residue was purified by prep-HPLC to afford 143 as a yellowsolid (50 mg, 45%). MS: (M+H)⁺ 614. ¹H NMR (500 MHz, MeOD) δ 1.79 (s,2H), 1.90 (s, 2H), 2.54-2.56 (t, J=6.5 Hz, 2H), 2.63-2.67 (m, 2H),2.86-2.88 (t, J=6 Hz, 2H), 3.59 (s, 2H), 3.70 (s, 3H), 3.76-3.79 (m,1H), 4.00-4.07 (m, 3H), 4.21 (s, 3H), 4.48-4.53 (m, 2H), 4.64-4.67 (t,J=6.5 Hz, 2H), 4.75-4.78 (t, J=7 Hz, 2H), 5.90 (s, 1H), 6.72 (s, 1H),7.20-7.27 (m, 3H), 7.91-7.92 (d, 1H).

Example 1445-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-(5-cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxopyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one144 Example 144a3-(5-Cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one144a

A mixture of5-bromo-3-(5-cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrazin-2-ylamino)-1-methylpyridin-2(1H)-one135c (0.9 g, 2.48 mmol), bis(pinacolato)diboron (1.26 g, 4.96 mmol),PdCl₂(dppf) (272 mg, 0.37 mmol) and KOAc (486 mg, 4.96 mmol) in1,4-dioxane (40 mL) was heated at reflux for 15 h. After the completionof the reaction, the mixture was filtered off, and washed with ethylacetate (100 mL). The filtrate was evaporated in vacuo and the residuewas purified on silica gel column to give 144a (407 mg, 40%). MS: [M+H]⁺412.

Example 144b5-[5-Fluoro-3-[1-methyl-5-(5-cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxopyridin-3-yl]benzylacetate]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one144b

A mixture of 144a (300 mg, 0.73 mmol),(2-bromo-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl)methylacetate (212a) (297 mg, 0.66 mmol), PdCl₂(dppf) (73 mg, 0.1 mmol), and2M Na₂CO₃ solution (2 mL) in DME (8 mL) was heated at 120° C. undermicrowave irradiation for 0.5 h. The solvent was evaporated in vacuo andthe residue was purified on reverse phase Combi-flash to give 144b (173mg, 40%). MS: [M+H]⁺ 657.

A mixture of 144b (170 mg, 0.26 mmol) and LiOH hydrate (104 mg, 2.6mmol) in ^(i)PrOH (15 mL) and H₂O (3 mL) was stirred at 30° C. for 2 h.The mixture was evaporated in vacuo and the residue was extracted withEtOAc (20 mL×2). The combined extracts were concentrated under reducedpressure. The residue was purified on prep-HPLC to give 144 (50 mg,31%). MS: [M+H]⁺ 615. ¹H NMR (500 MHz, MEOD) δ 7.89 (d, J=2.0, 1H), 7.26(d, J=2.0, 1H), 7.22-7.18 (m, 2H), 5.89 (s, 1H), 4.52-4.46 (m, 2H),4.17-4.11 (m, 1H), 4.02-3.97 (m, 3H), 3.82 (s, 2H), 3.69 (s, 3H),3.16-3.14 (m, 2H), 3.10-3.03 (m, 1H), 2.96-2.90 (m, 1H), 2.87-2.85 (m,2H), 2.65-2.53 (m, 2H), 1.97-1.85 (m, 5H), 0.62-0.58 (m, 2H), 0.53-0.50(m, 2H)

Example 1452-(2-(Hydroxymethyl)-3-(4-methyl-5-oxo-6-(4-(piperidin-4-yl)phenyl-amino)-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one145 Example 145a tert-Butyl4-(4-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-piperidine-1-carboxylate145a

Compound 145a was synthesized using the same procedure as Example 112a,except using tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (0.83g, 3.0 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (0.88 g, 3.3 mmol),cesium carbonate (1.27 g, 3.9 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.275 g, 0.3 mmol), Xantphos(0.26 g, 0.45 mmol) and 1,4-dioxane (30 mL). The reaction mixture washeated at 100° C. overnight. Work-up and purified by flash columnchromatography (silica, ethyl acetate/hexanes) to give a 80% yield (1.1g) of tert-butyl4-(4-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-piperidine-1-carboxylate145a as a solid: MS (ESI+) m/z 465.0 (M+H).

Example 145b

The compound mixture 145b was synthesized using the same procedure asExample 121b, except using2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (162 mg, 0.35 mmol), tert-butyl4-(4-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-piperidine-1-carboxylate145a (135 mg, 0.3 mmol), 1M sodium carbonate solution (1.2 mL, 1.2mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) and1,2-dimethoxyethane (3 mL). Work-up and flash column chromatography(silica, ethyl acetate/hexanes) afford 145b (120 mg) as yellow oil.

Example 145c

The compound mixture was synthesized using the same procedure as Example121c, except using 145b (120 mg), Trifluoroacetic acid (0.5 mL, 6.5mmol) in methylene chloride (7 mL). Workup and concentrated to drynessto gave compound 145c as yellow oil, which was used without purificationin the next step.

Compound 145 was synthesized using the same procedure as for Example121, except using a mixture of THF (1 mL), water (0.5 mL) andisopropanol (1 mL), compound 145c and lithium hydroxide monohydrate (50mg, 1.30 mmol). Work-up and flash column chromatography (silica,methylene chloride/20% TEA in methanol) give a yellow solid (68 mg),which was flushed out from a basic aluminum column (ethyl acetate) againto afford a 15% yield (3 steps, 25 mg) of 145 as a white solid: MS(ESI+) m/z 579.4 (M+H).

Example 1462-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one146 Example 146a5-Bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one146a

A suspension of5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 101e (1 g, 6.6mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.7 g, 6.6 mmol), XantPhos(380 mg, 0.66 mmol), Pd₂(dba)₃ (602 mg, 0.66 mmol) and Cs₂CO₃ (4 g, 13.2mmol) in dioxane (30 mL) was heated in a sealed tube at 120° C. for 2 hunder nitrogen. After reaction the solvent was filtered and the filtratewas evaporated in vacuo to give a yellow solid. The yellow solid waswashed with EtOAc (10 mL×3) to give 146a as a yellow solid (1 g, 45%),which was used without further purification. MS: (M+H)⁺ 338.

Example 146b2-(1-Methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 146b

A 25 mL vial was charged with5-bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one145a (500 mg, 1.48 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (664 mg, 1.48 mmol), CH₃COONa (243 mg, 2.96 mmol),PdCl₂(dppf) (121 mg, 0.148 mmol), and K₃PO₄ (790 mg, 2.96 mmol)suspended in CH₃CN (50 mL) and H₂O (3 mL). It was then heated at 110° C.for 12 h under argon atmosphere. After reaction the mixture wasevaporated and the residue was purified by reverse phase Combi-flasheluting with 0.3% NH₄HCO₃ in 1:5 water/CH₃CN to give 146b as a brownsolid (200 mg, 23%). MS: (M+H)⁺ 596.

To a solution of2-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexa-hydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 146b (180 mg, 0.3 mmol) in propan-2-ol (9 mL), tetrahydrofuran(9 mL), and water (3 mL) was added LiOH (726 mg, 30 mmol). The mixturewas stirred at 30° C. for 2 h. After reaction the mixture was evaporatedand the residue was purified by prep-HPLC to afford 146 as a white solid(67 mg, 41%). MS: (M+H)⁺ 554. ¹H NMR (500 MHz, MeOD) δ 1.80 (s, 2H),1.90 (s, 2H), 2.49 (s, 3H), 2.54-2.57 (t, 2H), 2.63-2.67 (m, 2H),2.93-2.96 (t, J=5.5 Hz, 2H), 3.64 (s, 2H), 3.70 (s, 3H), 4.02-4.06 (m,3H), 4.18-4.23 (m, 3H), 4.49-4.57 (m, 2H), 5.89 (s, 1H), 6.72 (s, 1H),7.23 (s, 1H), 7.36-7.38 (d, 1H), 7.41-7.42 (d, 1H), 7.49-7.52 (t, 1H),7.1 (s, 1H).

Example 1472-(3-(5-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one147 Example 147a6-Chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-2-methylpyridazin-3(2H)-one147a

A mixture of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine 110b (0.8g, 5.76 mmol), xantophos (360 mg, 0.623 mmol), Pd₂dba₃ (384 mg, 0.42mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one 103e (1.28 g, 5.76mmol) and Cs₂CO₃ (5.05 g. 17.3 mmol) in 1,4-dioxane (40 mL) was heatedat reflux for 2 h. After the completion of the reaction, the mixture wasfiltered off, and washed with MeOH (60 mL). The filtrate was evaporatedin vacuo. The residue was purified on reverse phase Combi-flash to give147a (1.3 g, 81%). MS: [M+H]⁺ 282.

Example 147b2-(5-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 147b

A mixture of6-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-2-methylpyridazin-3(2H)-one147a (400 mg, 1.42 mmol),2-(1-oxo-3,4,6,7,8,9-hexa-hydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzylacetate 114a (660 mg, 1.42 mmol), PdCl₂(dppf) (155 mg, 0.21 mmol), K₃PO₄(150 mg), and NaOAc (50 mg) in MeCN (20 mL) and H₂O (4 mL) was heated at110° C. in sealed tube for 2 h. The solvent was evaporated in vacuo andthe residue was purified on reverse phase Combi-flash to give 147b (273mg, 33%). MS: [M+H]⁺ 584.

A mixture of2-(5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 147b (410 mg, 0.7 mmol) and LiOH hydrate (590 mg, 14 mmol) in^(i)PrOH (20 mL) and H₂O (4 mL) was stirred at 30° C. for 2 h. Themixture was evaporated in vacuo and the residue was extracted with ethylacetate (20 mL×2). The combined extracts were concentrated under reducedpressure. The residue was purified on prep-HPLC to give 147 (120 mg,32%). MS: [M+H]⁺ 542. ¹H NMR (500 MHz, DMSO) δ 9.30 (s, 1H), 7.90 (s,1H), 7.49-7.46 (m, 1H), 7.41-7.37 (m, 2H), 6.51 (s, 1H), 6.04 (s, 1H),4.74 (s, 2H), 4.62-4.60 (m, 1H), 4.48-4.45 (m, 1H), 4.39-4.35 (m, 1H),4.18-4.06 (m, 3H), 4.04-3.95 (m, 4H), 3.90-3.85 (m, 1H), 3.75 (s, 3H),2.60-2.56 (m, 2H), 2.51-2.45 (m, 2H), 1.82-1.74 (m, 2H), 1.73-1.64 (m,2H).

Example 1482-(3-(5-(5-Fluoropyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one148 Example 148a5-Bromo-3-(5-fluoropyridin-2-ylamino)-1-methylpyridin-2(1H)-one 148a

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 1,4-dioxane (50 mL),5-fluoropyridin-2-amine (0.67 g, 6 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (1.34 g, 5 mmol) and cesiumcarbonate (4.89 g, 15 mmol). After bubbling nitrogen through theresulting solution for 30 minutes, XantPhos (576 mg, 1 mmol) andtris(dibenzylideneacetone)dipalladium(0) (460 mg, 0.5 mmol) were added,and the reaction mixture was heated at reflux for 15 h. After this timethe reaction was cooled to room temperature, partitioned between ethylacetate (100 mL) and water (100 mL) and filtered. The aqueous layer wasseparated and extracted with ethyl acetate (50 mL×2). The organic layerswere combined and washed with brine (50 mL) and dried over sodiumsulfate. The drying agent was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was washed withacetonitrile (30 mL) and filtered to afford 148a (900 mg, 61%). MS:[M+H]⁺ 298.

Example 148b2-(5-(5-Fluoropyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 148b

A sealed tube was charged with the mixture of2-(1-oxo-3,4,6,7,8,9-hexa-hydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (232 mg, 0.5 mmol), 148a (148 mg, 0.50 mmol), Pd(dppf)Cl₂(25 mg, 0.03 mmol), K₃PO₄.3H₂O (266 mg, 1.0 mmol), and NaOAc (82 mg, 1.0mmol) in CH₃CN (18 mL). The system was evacuated and refilled with N₂.The reaction mixture was heated at 110° C. for 2 h. It was then cooledto room temperature and filtered. The filtrate was concentrated underreduced pressure and the resulting residue was purified by flash columnchromatography eluting with 30:1 DCM/MeOH to afford 148b as a yellowsolid (200 mg, 72%). MS: [M+H]⁺ 556.

At room temperature, to the solution of 148b (200 mg, 0.36 mmol) inTHF/iPA/H₂O (6 mL/6 mL/2 mL) was added LiOH (87 mg, 3.6 mmol) whilestirring. This mixture was stirred for 0.5 h. Then, 20 mL H₂O was addedand extracted with ethyl acetate (30 mL×3). The combined organic layerwas dried with Na₂SO₄ and concentrated to get a yellow solid, which wasfurther purified by prep-HPLC to afford 148 as a white solid (110 mg,59%). LCMS: [M+H]⁺ 514. ¹H NMR (500 MHz, DMSO) δ 8.77 (s, 1H), 8.62 (d,J=2.0, 1H), 8.16 (d, J=2.5, 1H), 7.59 (m, 1H), 7.47 (t, J=7.5, 1H),7.39-7.14 (m, 2H), 7.34 (m, 2H), 6.52 (s, 1H), 4.85 (s, 1H), 4.35 (d,J=4.0, 2H), 4.17 (m, 2H), 4.10 (m, 1H), 3.90 (m, 1H), 3.61 (s, 3H), 2.60(m, 2H), 2.48 (m, 2H), 1.80 (t, J=5.5, 2H), 1.70 (m, 2H).

Example 1492-(3-(5-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one149 Example 149a2-(5-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 149a

A mixture of2-(acetoxymethyl)-5-fluoro-3-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)phenylboronicacid 210d (150 mg, 0.38 mmol),5-bromo-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methylpyridin-2(1H)-one110c (122 mg, 0.38 mmol), PdCl₂(dppf) (41 mg, 0.056 mmol), K₃PO₄ (100mg), and NaOAc (50 mg) in MeCN (10 mL) and H₂O (3 mL) was heated at 110°C. in a sealed tube for 2 h. The solvent was evaporated in vacuo and theresidue was purified on reverse phase Combi-flash to give 149a (120 mg,53%). MS: [M+H]⁺ 601.

A mixture of 149a (120 mg, 0.2 mmol) and LiOH hydrate (84 mg, 2 mmol) in^(i)PrOH (10 mL) and H₂O (3 mL) was stirred at 30° C. for 2 h. Themixture was evaporated in vacuo and the residue was extracted with ethylacetate (10 mL×2). The combined extracts were concentrated under reducedpressure and the residue was purified on prep-HPLC to give 149 (60 mg,54%). MS: [M+H]⁺ 559. ¹H NMR (500 MHz, MeOD) δ 7.82 (s, 1H), 7.16 (s,1H), 7.10 (d, J=9.0, 2H), 6.62 (s, 1H), 5.77 (s, 1H), 4.67 (s, 2H),4.43-4.35 (m, 2H), 4.11-4.07 (m, 3H), 4.00-3.99 (m, 2H), 3.93-3.90 (m,3H), 3.60 (s, 3H), 2.55-2.52 (m, 2H), 2.46-2.43 (m, 2H), 1.82-1.78 (m,2H), 1.71-1.67 (m, 2H).

Example 1505-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}pyridin-3-yl)phenyl]-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one150 Example 150a3-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one150a

A mixture of5-bromo-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methylpyridin-2(1H)-one110c (1.3 g, 4.0 mmol), bis(pinacolato)diboron (2.03 g, 8 mmol),PdCl₂(dppf) (439 mg, 0.6 mmol) and KOAc (784 mg, 8.0 mmol) in1,4-dioxane (60 mL) was heated at reflux for 15 h. After the completionof the reaction, the mixture was filtered off and washed with EtOAc (100mL). The filtrate was evaporated in vacuo and the residue was purifiedon silica gel column to give 150a (446 mg, 30%). MS: [M+H]⁺ 373.

Example 150b[4-Fluoro-2-(1-methyl-6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}pyridin-3-yl)-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 150b

A mixture of 150a (260 mg, 0.70 mmol),(2-bromo-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl)methylacetate 218a (225 mg, 0.50 mmol), PdCl₂(dppf) (55 mg, 0.075 mmol), 2 MNa₂CO₃ solution (1.5 mL) in DME (8 mL) was heated at 120° C. undermicrowave irradiation for 0.5 h. The solvent was evaporated in vacuo andthe residue was purified on reverse phase Combi-flash to give 150b (154mg, 50%). MS: [M+H]⁺ 618.

A mixture of 150b (150 mg, 0.24 mmol) and LiOH hydrate (96 mg, 2.4 mmol)in ^(i)PrOH (15 mL) and H₂O (3 mL) was stirred at 30° C. for 2 h. Themixture was evaporated in vacuo and the residue was extracted with ethylacetate (20 mL×2). The combined extracts were concentrated under reducedpressure. The residue was purified on prep-HPLC to give 150 (70 mg,51%). MS: [M+H]⁺ 576. ¹H NMR (500 MHz, DMSO) δ 8.22 (s, 1H), 8.00 (s,1H), 7.32-7.29 (m, 2H), 7.17-7.15 (m, 1H), 5.93 (s, 1H), 4.86-4.85 (m,1H), 4.71 (s, 2H), 4.36-4.28 (m, 2H), 4.10-3.84 (m, 7H), 3.57 (s, 3H),3.02-2.92 (m, 1H), 2.90-2.76 (m, 3H), 1.86-1.74 (m, 4H).

Example 1512-(3-(5-(5-(Azetidin-3-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one151 Example 151a2-(5-(5-(Azetidin-3-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 151a

In a 44-mL sealed tube equipped with a magnetic stirring bar were placed3-(5-(azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one155n (60 mg, 0.18 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (110 mg, 0.23 mmol), Pd(PPh₃)₄ (21 mg, 0.0.18 mmol) in 2 NNa₂CO₃ (3 mL), DME (2 mL), and dioxane (3 mL). After the reactionmixture was stirred at 100° C. for 14 h., it was partitioned betweendichloromethane (5 mL) and water (5 mL), and the organic phase wasextracted with dichloromethane (5 mL×3). The combined organic phaseswere washed with water (5 mL×2) and brine (5 mL×1), dried (Na₂SO₄), andconcentrated. The crude product was purified by flash chromatography(dichloromethane:MeOH, 85:15) to give 40% (40 mg) of2-(5-(5-(azetidin-3-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 151a as a solid.

A 25-mL, single-necked, round-bottomed flask equipped with a magneticstirring bar was charged with 151a (40 mg, 0.068 mmol), LiOH.H₂O (20 mg,0.48 mmol), THF (2 mL), i-PrOH (2 mL), and water (2 mL). After thereaction mixture was stirred at room temperature for 3 h, it waspartitioned between dichloromethane (5 mL) and water (5 mL), and theorganic phase was extracted with dichloromethane (5 mL×3). The combinedorganic phases were washed with water (5 mL×2) and brine (5 mL×1), dried(Na₂SO₄), and concentrated. The crude product was re-dissolved indichloromethane (3 mL). To this solution was added hexane (10 mL) andthe resulting precipitates were filtered to give 88% yield (33 mg) of151; MS(ESI⁺) m/z 551.3 (M+H).

Example 1522-(2-(Hydroxymethyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]benzoimidazole-1-one152 Example 152a N-(2-Hydroxyethyl)-1H-benzo[d]imidazole-2-carboxamide152a

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with1H-benzo[d]imidazole-2-carboxylic acid (1.50 g, 9.26 mmol) and thionylchloride (10 mL). After heating at reflux for 16 h, the suspension wascooled to room temperature and filtered. The filter cake was washed withtoluene (10 mL) and dried under vacuum at room temperature for 5 h. Theresulting solid was charged into a 100-mL single-neck round-bottomedflask equipped with a magnetic stirrer and reflux condenser, followed bychloroform (10 mL) and 2-hydroxyethylamine (559 mg, 9.17 mmol). Afterstirring at reflux for 16 h, the reaction mixture was concentrated underreduced pressure, and the resulting residue was triturated with water(20 mL) and dried in a vacuum oven at 45° C. to afford a 73% yield (1.41g) of 152a as a white solid: mp 194-195° C.; ¹H NMR (500 MHz, DMSO-d₆) δ13.13 (s, 1H), 8.74 (s, 1H), 7.71-7.29 (m, 4H), 4.80 (s, 1H), 3.55 (dd,2H, J=10.5, 5.5 Hz), 3.38 (dd, 2H, J=10.5, 5.5 Hz); MS (APCI+) m/z 206.6(M+H).

Example 152b 3,4-Dihydropyrazino[1,2-a]benzoimidazole-1-one 152b

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with152a (1.41 g, 6.84 mmol) and DMF (10 mL), and the reaction mixture wascooled to 0° C. A solution of thionyl chloride (896 mg, 7.53 mmol) inDMF (5 mL) was added dropwise. The reaction was heated at 150° C. for 2h. After this time, the solvent was removed under reduced pressure. Theresulting residue was partitioned between water (20 mL) and methylenechloride (20 mL). The layers were separated, and the aqueous phase wasextracted with methylene chloride (2×20 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by flashchromatography to afford a 52% yield (672 mg) of 152b as a brown solid:mp>250° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (s, 1H), 7.76 (d, 1H, J=9.0Hz), 7.66 (d, 1H, J=9.0 Hz), 7.40 (t, 1H, J=9.0 Hz), 7.31 (t, 1H, J=9.0Hz), 4.41 (t, 2H, J=6.0 Hz), 3.71 (m, 2H); MS (APCI+) m/z 188.4 (M+H).

Example 152c 3,4,6,7,8,9-Hexahydropyrazino[1,2-a]benzoimidazole-1-one152c

A 250-mL stainless steel pressure reactor was charged with 10% palladiumon carbon (50% wet, 150 mg dry weight) and a solution of 152b (670 mg,3.58 mmol) in acetic acid (25 mL). The reactor was evacuated, chargedwith hydrogen gas to a pressure of 350 psi and stirred at 95° C. for 16h. After this time, the hydrogen was evacuated, and nitrogen was chargedinto the reactor. Celite 521 (1.00 g) was added, and the mixture wasfiltered through a pad of Celite 521. The filter cake was washed withethanol (2×25 mL), and the combined filtrates were concentrated todryness under reduced pressure. To the resulting residue was added water(10 mL), and followed by potassium carbonate to adjust pH to 9. Themixture was extracted with methylene chloride (4×20 mL), and the organicextracts were combined, dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford a 71% yield 152c (487 mg)as a white solid: mp>250° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.86 (s, 1H),3.98 (t, 2H, J=6.5 Hz), 3.51 (m, 2H), 2.50 (m, 4H), 1.75 (m, 4H); MS(APCI+) m/z 192.6 (M+H).

Example 152d2-Bromo-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]benzoimidazole-2-yl)benzylAcetate 152d

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 152c(485 mg, 2.54 mmol), 104g (1.56 g, 5.08 mmol), cesium carbonate (1.66 g,5.08 mmol), N,N′-dimethylethylene-diamine (447 mg, 5.08 mmol) and1,4-dioxane (20 mL). After bubbling nitrogen through the resultingsuspension for 30 min, copper iodide (484 mg, 2.54 mmol) was added, andthe reaction mixture was heated at 100° C. (oil bath temperature) for 16h. After this time, the mixture was cooled to room temperature andfiltered. The filtrate was diluted with ethyl acetate (100 mL) and water(50 mL). The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography to afford a yellow oil,which was dissolved in methylene chloride (5 mL). Acetyl chloride (506mg, 2.54 mmol) and triethylamine (1.28 g, 12.7 mmol) were added, and thereaction mixture was stirred at room temperature for 2 h. After thistime, the reaction mixture was diluted with methylene chloride (50 mL)and saturated aqueous sodium bicarbonate (20 mL). The organic layer wasseparated, and the aqueous layer was extracted with methylene chloride(3×50 mL). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure to afford a 13% yield (140 mg)of 152d as a yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.60 (d, 1H, J=8.0Hz), 7.27 (t, 1H, J=8.0 Hz), 7.18 (d, 1H, J=8.0 Hz), 5.26 (d, 1H, J=12.0Hz), 5.14 (d, 1H, J=12.0 Hz), 4.32 (m, 1H), 4.24 (m, 1H), 4.14 (m, 1H),3.87 (m, 1H), 2.75 (m, 2H), 2.56 (m, 2H), 2.07 (s, 3H), 1.83 (m, 4H); MS(APCI+) m/z 418.8 (M+H).

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with152d (140 mg, 0.335 mmol), 104h (140 mg, 0.426 mmol), sodium carbonate(106 mg, 1.00 mmol), 1,4-dioxane (5 mL) and water (1 mL). This mixturewas degassed with nitrogen for 30 min.Tetrakis(triphenylphosphine)palladium (39 mg, 0.033 mmol) was added.After heating at 100° C. for 5 h, the reaction mixture was cooled toroom temperature and partitioned between water (40 mL) and methylenechloride (100 mL). The layers were separated, and the aqueous phase wasextracted with methylene chloride (2×50 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was dissolved in methanol (5mL), and potassium carbonate (500 mg, 3.62 mmol) was added. Afterstirring at room temperature for 2 h, the reaction mixture waspartitioned between water (20 mL) and methylene chloride (20 mL). Thelayers were separated, and the aqueous phase was extracted withmethylene chloride (2×20 mL). The organic extracts were combined, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by flash chromatography to afford 152in 9% yield (15 mg) as a yellow solid: mp 205-206° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 9.18 (s, 1H), 8.70 (d, 1H, J=2.5 Hz), 8.64 (m, 1H), 8.30 (d,1H, J=6.0 Hz), 7.51-7.47 (m, 2H), 7.39 (d, 1H, J=8.0 Hz), 7.35 (d, 1H,J=8.0 Hz), 7.31 (d, 1H, J=6.0 Hz), 4.92 (t, 1H, J=4.5 Hz), 4.36 (m, 2H),4.27 (m, 2H), 4.19 (m, 1H), 3.97 (m, 1H), 3.61 (s, 3H), 2.63 (m, 2H),2.52 (m, 2H), 1.87 (m, 4H); MS (ESI+) m/z 498.2 (M+H).

Example 1532-(2-(Hydroxymethyl)-3-(4-methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)-4,5-dihydropyrazin-2-yl)phenyl)-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-1(2H)-one153 Example 153a5-Bromo-1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one153a

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was purged with nitrogen and charged with120a (1.14 g, 2.62 mmol), methylene chloride (10 mL) and trifluoroaceticacid (10 mL). The solution was stirred for 2 h at room temperature.After this time, the solution was concentrated under reduced pressure.The residue was partitioned between methylene chloride (100 mL) and 1 Maqueous dibasic potassium phosphate (30 mL). The aqueous layer wasextracted with a 20% (v/v) solution of methanol in methylene chloride(3×100 mL). The organic extracts were combined, washed with brine (20mL) and dried over sodium sulfate. The drying agent was removed byfiltration, and the filtrate was concentrated under reduced pressure toafford a 68% yield (600 mg) of 153a as an off-white solid: mp 170-171°C.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 7.62 (m, 2H), 7.31 (s,1H), 6.97 (d, 1H, J=7.8 Hz), 4.10 (br s, 1H), 3.83 (s, 2H), 3.43 (s,3H), 2.96 (t, 2H, J=5.7 Hz), 2.68 (t, 2H, J=5.7 Hz); MS (ESI+) m/z 334.0(M+H).

A 50-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 153a(168 mg, 0.500 mmol), 111a (289 mg, 0.600 mmol), sodium carbonate (159mg, 1.50 mmol), DMF (5 mL), water (2.5 mL) and 1,4-dioxane (8 mL). Afterbubbling nitrogen through the resulting suspension for 30 min,tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.050 mmol) was added,and the reaction mixture was heated at reflux for 14 h. After this time,the mixture was cooled to room temperature, and methanol (2 mL), water(2 mL) and lithium hydroxide monohydrate (42 mg, 1.00 mmol) were added.The mixture was stirred for 4 h at room temperature and thenconcentrated in vacuo. The residue was partitioned between ethyl acetate(150 mL) and water (30 mL). The organic layer was separated, and theaqueous layer was extracted with a 20% (v/v) solution of methanol inmethylene chloride (3×150 mL). The combined organic layers were driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography (silica, 0% to 10%methanol/methylene chloride) to afford a 4% yield (12 mg) of 153 as anoff-white solid: 209-210° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (s,1H), 7.74 (s, 1H), 7.61 (d, 1H, J=7.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.46(t, 1H, J=8.0 Hz), 7.40 (s, 1H), 7.32 (d, 1H, J=7.4 Hz), 6.90 (d, 1H,J=8.3 Hz), 4.77 (m, 1H), 4.53 (m, 1H), 4.43 (m, 1H), 4.02 (m, 1H), 3.87(m, 1H), 3.77 (s, 2H), 3.58 (s, 3H), 2.91 (m, 4H), 2.79 (s, 2H), 2.63(m, 2H), 1.78 (m, 4H); MS (ESI+) m/z 568.1 (M+H).

Example 1542-(2-(Hydroxymethyl)-3-(6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-1(2H)-one154 Example 154a 5-Bromo-3-(pyrimidin-4-ylamino)pyridin-2(1H)-one 154a

A 250-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with2-aminopyrimidine (376 mg, 3.95 mmol), 3,5-dibromo pyridin-2(1H)-one(1.00 g, 3.95 mmol), 1 M THF solution of lithium hexamethyldisilazide(20 mL, 20.0 mmol), and 1,4-dioxane (25 mL). After bubbling nitrogenthrough the resulting suspension for 30 min, Xantphos (194 mg, 0.211mmol) and tris(dibenzylideneacetone)dipalladium(0) (165 mg, 0.197 mmol)were added, and the reaction mixture was heated at reflux for 3 h. Afterthis time, the mixture was cooled to room temperature and diluted withethyl acetate (150 mL) and water (30 mL). The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate (3×150mL). The combined organic extracts were dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography followed by trituration with ethyl acetate (20 mL) toafford a 24% yield (250 mg) of 154a as an off-white solid: mp 150-151°C.; ¹H NMR (500 MHz, DMSO-d₆) d 12.03 (s, 1H), 9.27 (s, 1H), 8.54 (s,1H), 8.20 (d, 1H, J=6.0 Hz), 7.85 (s, 1H), 6.64 (d, 1H, J=6.0 Hz); MS(ESI+) m/z 268.2 (M+H).

A 50-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 154a(175 mg, 0.655 mmol), 111a (315 mg, 0.655 mmol), sodium carbonate (208mg, 2.00 mmol), DMF (2.5 mL), water (1.2 mL) and 1,4-dioxane (4 mL).After bubbling nitrogen through the resulting suspension for 30 min,tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.065 mmol) was added,and the reaction mixture was heated at reflux for 14 h. After this time,the mixture was cooled to room temperature, and methanol (2 mL), water(2 mL) and lithium hydroxide monohydrate (82 mg, 1.95 mmol) were added.The mixture was stirred for 2 h at room temperature and thenconcentrated in vacuo. The residue was partitioned between ethyl acetate(150 mL) and water (30 mL). The organic layer was separated, and theaqueous layer was extracted with a 20% (v/v) solution of methanol inmethylene chloride (3×150 mL). The combined organic extracts were driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography (silica, 0% to 10%methanol/methylene chloride) to afford a 5% yield (15 mg) of 154 as anoff-white solid: mp 200-201° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.99 (s,1H), 9.34 (s, 1H), 8.57 (s, 1H), 8.21 (d, 1H, J=6.0 Hz), 8.00 (s, 1H),7.62 (s, 1H), 7.44 (t, 1H, J=7.5 Hz), 7.35 (d, 1H, J=7.0 Hz), 6.70 (d,1H, J=5.5 Hz), 5.05 (br s, 1H), 4.28 (t, 1H, J=11.0 Hz), 4.18 (d, 1H,J=10.0 Hz), 3.96 (m, 1H), 3.90 (m, 1H), 2.94 (m, 1H), 2.84 (m, 1H), 2.77(m, 2H), 1.76 (m, 4H); MS (ESI+) m/z 500.1 (M+H).

Example 1555,5,6,6,7,7-Hexadeutero-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-1(2H)-one155 Example 155c Ethyl4,4,5,5,6,6-Hexadeutero-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate155c

Intermediate 155a (1.53 g) was reacted with ethyl 2-mercaptoacetate(1.57 g) using the same general procedure as described in Example 105b.Intermediate 155c was obtained as a clear oil in 51% yield (1.46 g): ¹HNMR (500 MHz, CDCl₃) δ 7.46 (s, 1H), 4.31 (q, 2H, J=7.5 Hz), 2.77 (s,2H), 1.35 (t, 3H, J=7.5 Hz); MS (ESI+) m/z 217 (M+H).

Example 155d4,4,5,5,6,6-Hexadeutero-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylicAcid 155d

Intermediate 155d (1.34 g) was saponified using the same generalprocedure as described in Example 105c. Intermediate 155d was obtainedas a white solid in 94% yield (1.10 g): mp 192-193° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 12.75 (br s, 1H), 7.40 (s, 1H), 2.73 (s, 2H).

Example 155e4,4,5,5,6,6-Hexadeutero-N-methoxy-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide155e

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen, charged with 155d (5.67 g, 30.1 mmol),methylene chloride (100 mL), and DMF (110 mg, 1.50 mmol) and cooled to0° C. To the resulting solution, oxalyl chloride (4.21 g, 33.1 mmol) wasadded dropwise. After this addition was complete, the reaction waswarmed to room temperature and stirred for 3 h. After this time, thereaction was concentrated to dryness under reduced pressure. The residuewas dissolved in methylene chloride (100 mL), and the resulting solutionwas cooled to 0° C. Triethylamine (9.15 g, 90.3 mmol) andN,O-dimethylhydroxylamine hydrochloride (3.23 g, 33.1 mmol) were added.After the addition was complete, the cooling bath was removed, and thereaction mixture was stirred at room temperature for 14 h. After thistime, the reaction mixture was partitioned between water (100 mL) andethyl acetate (200 mL). The layers were separated, and the aqueous phasewas extracted with ethyl acetate (100 mL). The combined organic extractswere washed with water (100 mL), followed by brine (100 mL) and driedover sodium sulfate. The drying agent was removed by filtration, and thesolvent was evaporated under reduced pressure. The resulting residue waspurified by flash chromatography (silica, 0% to 100% ethylacetate/hexanes) to afford a 90% yield of 155e (6.29 g) as a whitesolid: mp 47-48° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.62 (s, 1H), 3.76 (s,3H), 3.31 (s, 3H), 2.77 (s, 2H); MS (ESI+) m/z 232.1 (M+H).

Example 155f1-(4,4,5,5,6,6-Hexadeutero-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)prop-2-en-1-one155f

A 250-mL single-necked round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 155e (6.29 g, 27.2mmol) and anhydrous THF (60 mL), and the resulting solution was cooledto −25° C. with acetone/ice bath. A 1.0 M solution of vinylmagnesiumbromide in THF (32.3 mL, 32.6 mmol) was added dropwise, and theresulting reaction mixture was stirred at 0° C. for 1 h. After thistime, the reaction mixture was partitioned between ethyl acetate (250mL) and 2 M hydrochloric acid (50 mL). The layers were separated, andthe aqueous phase was extracted with ethyl acetate (40 mL). The combinedorganic extracts were washed with water (100 mL), followed by brine (100mL), dried over sodium sulfate, filtered and concentrated under reducedpressure to afford a crude quantitative yield of 155f (5.39 g) as asemi-solid. The material was used in the next step without furtherpurification.

Example 155g3-Chloro-1-(4,4,5,5,6,6-hexadeutero-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)propan-1-one155g

A 250-mL single-necked round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 155f (5.39 g, 27.2mmol), methylene chloride (60 mL), and the resulting solution was cooledto 0° C. A 2 M solution of hydrogen chloride in diethyl ether (34 mL)was added. After stirring at room temperature for 3 h, the solvents wereremoved under reduced pressure. Purification of the resulting residue bycolumn chromatography (silica, 0% to 50% ethyl acetate/hexanes) affordeda quantitative yield (6.38 g) of 155g as an off-white solid: mp 51-53°C.; ¹H NMR (300 MHz, CDCl₃) δ 7.41 (s, 1H), 3.89 (t, 2H, J=7.0 Hz), 3.30(t, 2H, J=7.0 Hz), 2.79 (s, 2H); MS (ESI+) m/z 235.1 (M+H).

Example 155h6,6,7,7,8,8-Hexadeutero-5,6,7,8-tetrahydro-1H-benzo[b]cyclopenta[d]thiophen-3(2H)-one155h

A 250-mL single-necked round-bottomed flask equipped with a magneticstirrer was charged with 155g (6.38 g, 27.2 mmol) and 98% sulfuric acid(50 mL). After stirring at 95° C. for 14 h, the reaction mixture waspoured into ice (50 g), and the resulting suspension was extracted withethyl acetate (3×50 mL). The organic extracts were combined, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography (silica, 0% to50% ethyl acetate/hexanes) to afford 155h in a 56% yield (3.03 g) as anoff-white solid: mp 43-44° C.; ¹H NMR (300 MHz, CDCl₃) δ 2.91 (m, 6H).

Example 155i6,6,7,7,8,8-Hexadeutero-5,6,7,8-tetrahydro-1H-benzo[b]cyclopenta[d]thiophen-3(2H)-oneOxime 155i

A 250-mL single-neck round-bottomed flask equipped with a mechanicalstirrer and nitrogen inlet was charged with hydroxylamine hydrochloride(1.59 g, 22.9 mmol) and methanol (40 mL). The mixture was cooled to 0°C. using an ice bath. Sodium acetate trihydrate (3.19 g, 22.9 mmol) wasadded. The mixture was stirred at 0° C. for 30 min. After this time,155h (3.03 g, 15.3 mmol) was added, and the reaction was stirred at roomtemperature for 14 h. After this time, the mixture was concentrated,redissolved in methylene chloride (200 mL) with water (30 mL). Theorganic layer was separated, and the aqueous layer was extracted withmethylene chloride (3×150 mL). The combined organic layers were driedover sodium sulfate and concentrated under reduced pressure to afford a84% yield (2.72 g) of 155i as an off-white solid: mp 174-176° C.; ¹H NMR(300 MHz, CDCl₃) δ 3.12 (m, 2H), 2.82 (m, 4H); MS (ESI+) m/z 214.1(M+H).

Example 155j5,5,6,6,7,7-Hexadeutero-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-1(2H)-one155j

A 50-mL single-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 155i(2.72 g, 12.8 mmol) and polyphosphoric acid (150 g). After stirring at80° C. for 14 h, the reaction mixture was cooled to room temperature,and water (300 mL) was added. The resulting mixture was stirred for 30min and filtered. The filter cake was washed with water (20 mL) anddried in a vacuum oven at 45° C. to afford a 74% yield (2.00 g) of 155jas an off-white solid: mp 204-205° C.; ¹H NMR (300 MHz, CDCl₃) δ 5.58(s, 1H), 3.58 (m, 2H), 2.79 (s, 2H), 2.71 (t, 2H, J=7.0 Hz); MS (ESI+)m/z 214.1 (M+H).

Example 155k2-Bromo-6-(5,5,6,6,7,7-hexadeutero-1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzylAcetate 155k

A 250-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 155j(1.00 g, 4.69 mmol), 104g (2.89 g, 9.38 mmol), cesium carbonate (4.59 g,14.1 mmol), N,N′-dimethylethylene-diamine (412 mg, 4.69 mmol) and1,4-dioxane (35 mL). After bubbling nitrogen through the resultingsuspension for 30 min, copper iodide (447 mg, 2.35 mmol) was added, andthe reaction mixture was heated at 80° C. (oil bath temperature) for 20h. After this time, the mixture was cooled to room temperature andfiltered. The filtrate was diluted with ethyl acetate (150 mL) and water(30 mL). The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography (silica, 0% to 40%ethyl acetate/hexanes) to afford a 35% yield (715 mg) of 155k as anoff-white solid: mp 74-75° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.59 (m, 1H),7.31 (m, 2H), 5.15 (d, 1H, J=12.0 Hz), 5.04 (d, 1H, J=12.0 Hz), 3.99 (m,1H), 3.65 (m, 1H), 2.81 (m, 1H), 2.74 (s, 2H), 2.06 (s, 3H); MS (ESI+)m/z 440.1 (M+H).

Example 155l2-(5,5,6,6,7,7-Hexadeutero-1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylAcetate 155l

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with155k (710 mg, 1.61 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (819 mg,3.22 mmol), potassium acetate (474 mg, 4.83 mmol) and 1,4-dioxane (12mL). After bubbling nitrogen through the resulting suspension for 30min, [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (118mg, 0.161 mmol) was added, and the reaction mixture was heated at refluxfor 2 h. After this time, the mixture was cooled to room temperature anddiluted with ethyl acetate (150 mL) and water (30 mL). The organic layerwas separated, and the aqueous layer was extracted with ethyl acetate(3×150 mL). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure to afford a crude 155l (785 mg)in a quantitative yield. The material was used in the next step withoutfurther purification.

Example 155m tert-Butyl3-(6-(6-Bromo-2-methyl-3-oxo-2,3-dihydropyrin-4-ylamino)pyridin-3-yl)azetidine-1-carboxylate155m

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with tert-butyl3-(6-aminopyridin-3-yl)azetidine-1-carboxylate (333 mg, 1.33 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (350 mg, 1.33 mmol), cesiumcarbonate (870 mg, 2.70 mmol) and 1,4-dioxane (10 mL). After bubblingnitrogen through the resulting solution for 30 min, Xantphos (66 mg,0.114 mmol) and tris(dibenzylideneacetone)dipalladium(0) (61 mg, 0.066mmol) were added and the reaction mixture was heated at 105° C. for 3 h.After this time, the mixture was cooled to room temperature andfiltered. The filter cake was washed with methylene chloride (2×10 mL),and the combined filtrates were concentrated under reduced pressure. Theresulting residue was purified by column chromatography on silica toafford a 79% yield (460 mg) of 155m as a green solid: mp 134-136° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 7.66(dd, 1H, J=8.5, 2.0 Hz), 7.51 (s, 1H), 7.35 (d, 1H, J=8.5 Hz), 4.21 (t,2H, J=8.0 Hz), 3.81 (m, 2H), 3.51 (s, 3H), 1.40 (s, 9H); MS (ESI+) m/z436.1 (M+H).

Example 155n3-(5-(Azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one155n

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was purged with nitrogen and charged with155m (1.20 g, 2.76 mmol), methylene chloride (10 mL) and trifluoroaceticacid (10 mL). The solution was stirred for 2 h at room temperature.After this time, the solution was concentrated under reduced pressure.The residue was partitioned between methylene chloride (100 mL) and 1 Maqueous dibasic potassium phosphate (30 mL). The aqueous layer wasextracted with a 20% (v/v) solution of methanol in methylene chloride(3×100 mL). The organic extracts were combined, washed with brine (20mL) and dried over sodium sulfate. The drying agent was removed byfiltration, and the filtrate was concentrated under reduced pressure toafford a quantitative yield (920 mg) of 155n as an off-white solid: mp123-124° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.65 (d, 1H,J=2.3 Hz), 8.19 (d, 1H, J=2.1 Hz), 7.71 (dd, 1H, J=8.6, 2.2 Hz), 7.51(d, 1H, J=2.3 Hz), 7.33 (d, 1H, J=8.2 Hz), 3.74 (m, 3H), 3.58 (m, 2H),3.52 (s, 3H); MS (ESI+) m/z 335.1 (M+H).

Example 155o2-(5-(5-(Azetidin-3-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(5,5,6,6,7,7-hexadeutero-1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzylAcetate 155o

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with crude155l (785 mg, presumed 1.61 mmol), 155n (450 mg, 1.34 mmol), sodiumcarbonate (426 mg, 4.02 mmol), DMF (10 mL), water (5 mL) and 1,4-dioxane(16 mL). After bubbling nitrogen through the resulting suspension for 30min, tetrakis(triphenylphosphine)palladium(0) (155 mg, 0.134 mmol) wasadded, and the reaction mixture was heated at reflux for 14 h. Theresidue was partitioned between ethyl acetate (150 mL) and water (30mL). The organic layer was separated, and the aqueous layer wasextracted with a 20% (v/v) solution of methanol in methylene chloride(3×150 mL). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure to afford crude 155o. Thematerial was used in the next step without further purification.

Example 155p2-(3-(5-(5-(Azetidin-3-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-5,5,6,6,7,7-hexadeutero-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-1(2H)-one155p

A 100-mL single-neck round-bottomed flask equipped with a was chargedwith crude 155o from the previous step, THF (8 mL), methanol (4 mL),water (4 mL) and lithium hydroxide monohydrate (420 mg, 10.0 mmol) wereadded. The mixture was stirred for 4 h at room temperature and thenconcentrated in vacuo. The residue was partitioned between ethyl acetate(150 mL) and water (30 mL). The organic layer was separated, and theaqueous layer was extracted with a 20% (v/v) solution of methanol inmethylene chloride (3×150 mL). The combined organic layers were driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography (silica, 0% to 10%methanol/methylene chloride) to afford a 15% yield (140 mg) of 155p asan off-white solid: mp 140-142° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.65 (d,1H, J=2.0 Hz), 8.53 (s, 1H), 8.10 (d, 1H, J=2.4 Hz), 7.67 (m, 1H), 7.45(t, 1H, J=8.0 Hz), 7.31 (m, 4H), 4.81 (t, 1H, J=5.0 Hz), 4.35 (m, 2H),4.04 (m, 1H), 3.88 (m, 1H), 3.71 (m, 3H), 3.59 (s, 3H), 3.55 (m, 2H),2.96 (m, 1H), 2.86 (m, 1H), 2.77 (s, 2H); MS (ESI+) m/z 574.3 (M+H).

A 150-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen, charged with 155p (140 mg, 0.244mmol), 37% solution of formaldehyde in water (26 mg, 0.317 mmol) andmethanol (10 mL). A suspension of sodium cyanoborohydride (48 mg, 0.732mmol) and zinc chloride (50 mg, 0.366 mmol) in methanol (4 mL) wasadded, and the reaction was stirred at room temperature for 16 h. Afterthis time, the reaction mixture was concentrated in vacuo. The residuewas partitioned between ethyl acetate (150 mL) and water (30 mL). Theorganic layer was separated, and the aqueous layer was extracted with a20% (v/v) solution of methanol in methylene chloride (3×150 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography (silica, 0% to 10% methanol/methylene chloride) to afforda 45% yield (65 mg) of 155 as a white solid: mp 190-192° C.; ¹H NMR (500MHz, DMSO-d₆) δ 8.65 (d, 1H, J=2.5 Hz), 8.58 (s, 1H), 8.15 (d, 1H, J=2.5Hz), 7.67 (dd, 1H, J=8.5, 2.5 Hz), 7.46 (t, 1H, J=8.0 Hz), 7.33 (m, 4H),4.81 (t, 1H, J=4.0 Hz), 4.35 (m, 2H), 4.02 (m, 1H), 3.85 (m, 3H), 3.64(m, 1H), 3.59 (s, 3H), 3.42 (m, 2H), 2.98 (m, 1H), 2.87 (m, 1H), 2.76(s, 2H), 2.47 (s, 3H); MS (ESI+) m/z 588.2 (M+H).

Example 1562-(3-(5-(5-((3,3-Difluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one156 Example 156a Methyl 5-Nitro-1H-pyrazole-3-carboxylate 156a

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with5-nitro-1H-pyrazole-3-carboxylic acid (0.86 g, 5.5 mmol) and anhydrousmethanol (10 mL), and the reaction mixture was cooled to 0° C. in anice/water cooling bath. To the resulting solution thionyl chloride (1.7g, 14.4 mmol) was added dropwise. After the addition was complete, thebath was removed, and the reaction was heated at reflux for 3 h. Afterthis time, the reaction was concentrated to dryness under reducedpressure to afford a quantitative yield of 156a (0.94 g) as a whitesolid: MS (ESI−) m/z 170 (M−H).

Example 156b Methyl 1-Methyl-3-nitro-1H-pyrazole-5-carboxylate 156b

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with methyl5-nitro-1H-pyrazole-3-carboxylate (156a) (0.94 g, 5.5 mmol), anhydrousN,N-dimethylformamide (11 mL), methyl iodide (0.85 g, 6 mmol) andpotassium carbonate (0.83 g, 6.1 mmol). The reaction was stirred at roomtemperature for 16 h. After this time the reaction was diluted withwater (40 mL) and extracted with methylene chloride (3×25 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was subjectedto flash chromatography (silica, ethyl acetate/hexanes) to afford methyl1-methyl-3-nitro-1H-pyrazole-5-carboxylate 156b in 66% yield (0.67 g) asa white solid: MS (ESI+) m/z 186.0 (M+H). Also isolated was theregioisomer methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate in 15%yield (0.15 g) as a white solid: MS (ESI−) m/z 186.0 (M+H).

Example 156c (1-Methyl-3-nitro-1H-pyrazol-5-yl)methanol 156c

A 100-mL three-neck round-bottomed flask equipped with a magneticstirrer, addition funnel and nitrogen inlet was purged with nitrogen andcharged with 156b (0.67 g, 3.6 mmol), THF (20 mL) and cooled to 0° C.using an ice bath. 2 M lithium borohydride solution (3.6 mL, 7.2 mmol)was added dropwise at a rate that maintained the internal reactiontemperature below 5° C. After the addition was complete, the coolingbath was removed and the reaction was stirred at room temperature for 3h. The reaction was cooled to 0° C. using an ice bath, and saturatedaqueous sodium bicarbonate (30 mL) was added dropwise. The layers wereseparated, and aqueous layer was extracted with ethyl acetate (3×30 mL).The combined organic layers were washed with brine (30 mL), dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica, ethyl acetate/hexanes) toafford a quant. yield (0.56 g) of(1-methyl-3-nitro-1H-pyrazol-5-yl)methanol (156c) as an off-white solid:MS (ESI+) m/z 158.1 (M+H).

Example 156d 5-(Bromomethyl)-1-methyl-3-nitro-1H-pyrazole 156d

A 25-mL round-bottomed flask equipped with a magnetic stirrer and refluxcondenser was purged with nitrogen and charged with 156c (0.56 g, 3.6mmol) and chloroform (10 mL). The reaction was cooled to 0° C. using anice bath and phosphorous tribromide (0.98 g, 3.6 mmol) was addeddropwise. The cooling bath was removed and the reaction stirred atreflux for 3 h. After this time, the reaction was cooled to 0° C. anddiluted with methylene chloride (25 mL). Saturated aqueous sodiumbicarbonate was added until a pH of 8.5 was reached. The layers wereseparated, and the aqueous layer was extracted with methylene chloride(3×25 mL). The combined organic layers were washed with brine (30 mL),dried over sodium sulfate and concentrated under reduced pressure toafford a quantitative yield (0.79 g) of 156d as an off-white solid: MS(ESI+) m/z 222.1 (M+H).

Example 156e5-((3,3-Difluoroazetidin-1-yl)methyl)-1-methyl-3-nitro-1H-pyrazole 156e

A sealed tube with a magnetic stirrer was charged with DMF (5 mL),5-(Bromomethyl)-1-methyl-3-nitro-1H-pyrazole 156d (0.39 g, 1.78 mmol),3,3-difluoroazetidine hydrochloride (276 mg, 2.13 mmol) and DIPEA (0.8mL, 4.45 mmol). The reaction mixture was heated at 65° C. for 3-5 h.After this time the reaction was concentrated to dryness under reducedpressure, and the resulting residue was diluted with a mixture of EthylAcetate (15 mL) and water (15 mL). The aqueous layer was separated andextracted with Ethyl Acetate (2×15 mL). The combined organic extractswere dried over sodium sulfate and concentrated under reduced pressureto afford a quantitative yield of 156e as yellow oil, which was usedwithout further purification for the next step. MS (ESI+) m/z 233.0(M+H).

Example 156f5-((3,3-Difluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazol-3-amine 156f

A Parr reactor bottle was purged with nitrogen and charged with 10%palladium on carbon (30% wet, 150 mg dry weight) and a solution of 156e(1.78 mmol) in ethanol (25 mL). The bottle was attached to a Parrhydrogenator, evacuated, charged with hydrogen gas to a pressure of 40psi and shaken for 2 h. After this time, the hydrogen was evacuated, andthe reaction mixture was filtered through a pad of Celite 521. Thefilter cake was washed with ethanol (2×25 mL), and the combinedfiltrates were concentrated to dryness under reduced pressure to afforda quantitative yield of 156f (360 mg) as yellow oil: MS (ESI+) m/z 203.1(M+H).

Example 156g5-Bromo-3-(5-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one156g

Intermediate 156g was synthesized using the same procedure as Example112a, except using 156f (360 mg, 1.78 mmol),3,5-dibromo-1-methyl-1H-pyridin-2-one (0.43 g, 1.6 mmol), cesiumcarbonate (1.56 g, 4.8 mmol), tris(dibenzylideneacetone)dipalladium(0)(0.15 g, 0.16 mmol), Xantphos (0.18 g, 0.32 mmol) and 1,4-dioxane (18mL). The reaction mixture was heated at 115° C. for 24 hours. Work-upand flash column chromatography (silica, 60:35:5 methylenechloride/diethyl ether/methanol) give 38% yield (0.23 g) of 156g as agreen solid: MS (ESI+) m/z 390.1 (M+H).

Following Example 121c, except using2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (165 mg, 0.35 mmol), 156g (115 mg, 0.3 mmol), 1M sodiumcarbonate solution (1.2 mL, 1.2 mmol),tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) and1,2-Dimethoxyethane (3 mL). Work-up and flash column chromatography(silica, 60:35:5 methylene chloride/diethyl ether/methanol) afford 156h(a mixture of compound 156 and its acetate) as yellow oil (190 mg). Themixture (0.3 mmol) was deprotected using a mixture of THF (2 mL), water(1 mL) and isopropanol (2 mL), and Lithium hydroxide monohydrate (80 mg,1.90 mmol). Work-up and flash column chromatography (silica, 60:35:5methylene chloride/diethyl ether/methanol) afford a 12% yield (2 steps,22 mg) of 156 as a white solid: MS (ESI+) m/z 604.4 (M+H).

Example 1572-(2-(Hydroxymethyl)-3-(5-(5-methoxy-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one157 Example 157a5-Bromo-3-(5-methoxy-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one157a

A sealed tube was equipped with a magnetic stirrer and charged with5-methoxy-1H-pyrazol-3-amine (1.9 g, 17 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (4.9 g, 18 mmol) and cesiumcarbonate (12 g, 37 mmol) in 1,4-dioxane (160 mL). After bubblingnitrogen through the solution for 30 min, Xantphos (1.1 g, 2 mmol) andtris(dibenzylideneacetone)dipalladium(0) (1.1 g, 1.2 mmol) were added,and the reaction mixture was heated to 100° C. for 16 hours. After thistime, H₂O (50 mL) and EtOAc (50 mL) were added. The aqueous layer wasseparated and extracted with EtOAc (2×50 mL). The combined organicextracts were washed with brine (100 mL) and dried over sodium sulfate.The resulting solution was concentrated under reduced pressure to neardryness and the desired product fell out of solution. Filtering andwashing with Et₂O (10 mL) afforded 12% yield (590 mg) of crude 157a.

Example 157b2-(5-(5-Methoxy-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 157b

A microwave tube equipped with a magnetic stirrer was charged with 157a(94 mg, 0.3 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (180 mg, 0.4 mmol), DME (4 mL) and 1M aqueous sodiumcarbonate (0.9 mL). After bubbling N₂ for 15 min, Pd(PPh₃)₄ (18 mg, 0.02mmol) was added. The mixture was heated in microwave to 130° C. for 25min. After this time, EtOAc (5 mL) and water (5 mL) were added. Theseparated aqueous layer was extracted with EtOAc (2×5 mL). The combinedorganics were washed with brine (10 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography eluting with a gradient ofCH₂Cl₂—60:35:5 CH₂Cl₂:Et₂O:MeOH to afford a 19% yield (33 mg) of 157b.

A 25 mL round bottom flask with a magnetic stirrer was charged with 157b(33 mg, 0.06 mmol), lithium hydroxide (10 mg, 1.2 mmol), THF (0.3 mL),i-PrOH (0.3 mL) and water (0.6 mL). The mixture stirred at rt for 1 h.After this time, EtOAc (5 mL) and water (5 mL) were added. The separatedaqueous layer was extracted with EtOAc (2×5 mL). The combined organicswere washed with brine (10 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography eluting with a gradient of CH₂Cl₂—60:35:5CH₂Cl₂:Et₂O:MeOH to afford a 76% yield (23 mg) of 157. MS (ESI+) m/z515.4 (M+H).

Example 1585-[2-(Hydroxymethyl)-3-[1-methyl-6-oxo-5-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one158 Example 158a tert-Butyl2-(Diphenylmethyleneamino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate158a

To a round-bottomed flask equipped with a stirring bar, tert-butyl2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.09 g, 4.05mmol), diphenyl-methanimine 26 (2.20 g, 12.14 mmol), Pd(OAc)2 (181.6 mg,0.809 mmol), BINAP (503.8 mg, 0.809 mmol), Cs₂CO₃ (6.59 g, 20.23 mmol)and toluene (16 mL) were added. The reaction mixture was heated at 110°C. for 2 days. The reaction mixture was filtered and removed solvent invacuo. The residue 158a was directly used in the next step.

Example 158b tert-Butyl2-Amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate 158b

Intermediate 158a was added to a round-bottomed flask. MeOH (50 mL) andNH₂OH HCl (1.76 g, 25.3 mmol) was added. The resulting mixture wasstirred at RT for 5 hrs. The solvents were removed in vacuo and silicagel column (MeOH:DCM=10:90) gave 158b as dark oil, 851 mg (84%, 2steps).

Example 158c tert-Butyl2-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate158c

To a round-bottomed flask equipped with a stirring bar, 158b (851 mg,3.41 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.37 g, 5.12 mmol),Pd₂(dba)₃ (312.5 mg, 0.341 mmol), XantPhos (316 mg, 0.546 mmol), Cs₂CO₃(3.67 g, 11.3 mmol) and dioxane (17 mL) were added. The reaction mixturewas heated at 100° C. overnight. DCM (200 mL) was added to the resultingmixture was washed with water (30 mL×3). DCM (200 mL) was added and theresulting mixture was washed with water (30 mL×3), brine (30 mL×1),dried over MgSO₄, filtered, and removed solvent in vacuo. DCM/ether(1:2, 5 mL) was added followed by sonication, the precipitation wasfiltered as 158c, green solids, 865 mg (58%).

Example 158d5-[2-(Acetoxymethyl)-3-[1-methyl-6-oxo-5-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one158d

To a microwave tube equipped with a stirring bar, 158c (300 mg, 0.689mmol), boronic ester 111a (365 mg, 0.758 mmol), Pd(PPh₃)₄ (39.8 mg,0.034 mmol), Na₂CO₃ aqueous solution (1.0 N, 2.27 mL. 2.27 mmol),1,2-dimethoxyethane (3.0 mL) were added. The mixture was reacted inmicrowave at 130° C. for 10 min. methylene chloride (200 mL) was addedand the resulting mixture was washed with water (30 mL×3), brine (30mL×1), dried over MgSO₄, filtered, and removed solvent in vacuo. Silicagel column chromatography (MeOH:methylene chloride=5:95) gave 158d.

To a round-bottomed flask equipped with a stirring bar, 158d, THF (5mL), i-propanol (5 mL), water (5 mL), LiOH monohydrate (278 mg) wereadded. The resulting mixture was stirred at room temperature for 1 hr.The solvent was removed in vacuo and the resulting residue was added tomethylene chloride (200 mL), the solution was washed with water (30mL×3), brine (30 mL×1), dried over MgSO₄, filtered, and removed solventin vacuo. Silica gel column chromatography (methanol:methylenechloride=10:90) gave 158 as a yellow solid (145 mg). MS (ESI+) m/z 568.3(M+H).

Example 1592-(2-(Hydroxymethyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]imidazo[4,5-c]pyridine-1-one159 Example 159a 3-Nitro-4-(piperidin-1-yl)pyridine 159a

A 500-mL single-neck round-bottomed flask equipped with a refluxcondenser and magnetic stirrer was purged with nitrogen and charged with3-nitro-4-chloro-pyridine (10.0 g, 63.3 mmol), piperidine (16.2 g, 190mmol) and ethanol (200 mL). After heating at 70° C. for 2 h, the solventwas removed under reduced pressure, and the residue was partitionedbetween ethyl acetate (200 mL) and 10% aqueous potassium carbonate (100mL). The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate (2×100 mL). The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography to afford a 100% yield(15.2 g) of 159a as a yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 8.81 (s,1H), 8.31 (d, 1H, J=6.0 Hz), 6.86 (d, 1H, J=6.0 Hz), 3.22 (t, 4H, J=4.5Hz), 1.72 (m, 6H); MS (APCI+) m/z 208.4 (M+H).

Example 159b 6,7,8,9-Tetrahydropyrido[3,4-b]imidazo[4,5-c]pyridine 159b

A 500-mL single-neck round-bottomed flask equipped with a refluxcondenser and magnetic stirrer was purged with nitrogen and charged with159a (6.00 g, 29.0 mmol) and triethyl phosphite (200 mL). After heatingat 110° C. for 24 h, the triethyl phosphite was removed under reducedpressure, and the residue was partitioned between methylene chloride(200 mL) and water (100 mL). The organic layer was separated, and theaqueous layer was extracted with methylene chloride (2×100 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography to afford a 53% yield (2.66 g) of 159b as a yellow solid:mp 94-95° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.98 (s, 1H), 8.37 (d, 1H, J=6.0Hz), 7.22 (d, 1H, J=6.0 Hz), 4.09 (t, 2H, J=6.0 Hz), 3.11 (t, 2H, J=6.0Hz), 2.15 (m, 2H), 2.05 (m, 2H); MS (APCI+) m/z 174.1 (M+H).

Example 159c 6,7,8,9-Tetrahydropyrido[3,4-b]imidazo[4,5-c]pyridine2-Oxide 159c

A 100-mL single-neck round-bottomed flask equipped with a refluxcondenser and magnetic stirrer was charged with 159b (2.50 g, 14.4 mmol)and methylene chloride (50 mL), and the reaction mixture was cooled to0° C. 3-chloroperbenzoic acid (4.99 g, 28.9 mmol) was added, and themixture was stirred at room temperature for 1.5 h. After this time, thesolvent was removed under reduced pressure, and the residue was purifiedby column chromatography to afford an 83% yield (2.26 g) of 159c as ayellow solid: mp 178-179° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.71 (s, 1H),8.15 (d, 1H, J=6.0 Hz), 7.19 (d, 1H, J=6.0 Hz), 4.12 (t, 2H, J=6.0 Hz),3.12 (t, 2H, J=6.0 Hz), 2.18 (m, 2H), 2.05 (m, 2H); MS (APCI+) m/z 190.4(M+H).

Example 159d 6,7,8,9-Tetrahydropyrido[3,4-b]imidazo[4,5-c]pyridine-1-one159d

A 250-mL single-neck round-bottomed flask equipped with a refluxcondenser and magnetic stirrer was purged with nitrogen and charged with159c (2.26 g, 12.0 mmol) and acetic anhydride (90 mL). After heating at140° C. for 1.5 h, the solvent was removed under reduced pressure, andthe residue was purified by column chromatography to afford a 62% yield(1.40 g) of 159d as a yellow solid: mp>250° C.; ¹H NMR (500 MHz, CDCl₃)δ 11.3 (s, 1H), 7.24 (d, 1H, J=7.0 Hz), 6.39 (d, 1H, J=6.0 Hz), 4.07 (t,2H, J=6.0 Hz), 3.11 (t, 2H, J=6.0 Hz), 2.13 (m, 2H), 2.02 (m, 2H); MS(APCI+) m/z 190.7 (M+H).

Example 159e3,4,6,7,8,9-hexahydropyrido[3,4-b]imidazo[4,5-c]pyridine-1-one 159e

A 250-mL stainless steel pressure reactor was charged with 10% palladiumon carbon (50% wet, 250 mg dry weight) and a solution of 159d (1.07 g,5.66 mmol) in acetic acid (50 mL). The reactor was evacuated, chargedwith hydrogen gas to a pressure of 350 psi and stirred at 85° C. for 48h. After this time, the hydrogen was evacuated, and nitrogen was chargedinto the reactor. Celite 521 (1.00 g) was added, and the mixture wasfiltered through a pad of Celite 521. The filter cake was washed withethanol (2×25 mL), and the combined filtrates were concentrated todryness under reduced pressure. To the resulting residue was added water(10 mL), followed by potassium carbonate to adjust pH to 9. The mixturewas extracted with methylene chloride (4×20 mL), and the organicextracts were combined, dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford a 69% yield of 159e (749mg) as a white solid: mp>250° C.; ¹H NMR (500 MHz, CDCl₃) δ 5.28 (s,1H), 3.85 (t, 2H, J=6.0 Hz), 3.62 (m, 2H), 2.92 (t, 2H, J=6.0 Hz), 2.81(t, 2H, J=6.0 Hz), 2.03 (m, 2H), 1.94 (m, 2H); MS (APCI+) m/z 192.7(M+H).

Example 159f2-Bromo-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]imidazo[4,5-c]pyridine-2-yl)benzylAcetate 159f

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 159e(745 mg, 3.90 mmol), 104g (2.40 g, 7.80 mmol), cesium carbonate (2.54 g,7.80 mmol), copper iodide (743 mg, 3.90 mmol), and1-methyl-2-pyrrolidinone (7 mL). After heating at 120° C. (oil bathtemperature) for 16 h, the mixture was cooled to room temperature andpartitioned between methylene chloride (100 mL) and water (50 mL). Theorganic layer was separated, and the aqueous layer was extracted withmethylene chloride (3×50 mL). The combined organic layers were driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography to afford a yellow oil, which wasdissolved in methylene chloride (5 mL). Acetyl chloride (306 mg, 3.90mmol) and triethylamine (1.97 g, 19.5 mmol) was added, and the reactionmixture was stirred at room temperature for 2 h. After this time, thereaction mixture was diluted with methylene chloride (50 mL) andsaturated aqueous sodium bicarbonate (20 mL). The organic layer wasseparated, and the aqueous layer was extracted with methylene chloride(3×50 mL). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure to afford a 6% yield (100 mg) of159f as a pink oil: ¹H NMR (500 MHz, CDCl₃) δ 7.60 (d, 1H, J=8.0 Hz),7.34 (t, 1H, J=8.0 Hz), 7.16 (d, 1H, J=8.0 Hz), 5.18 (m, 2H), 4.18 (m,1H), 4.04 (m, 1H), 3.87 (m, 1H), 3.79 (m, 1H), 3.16 (m, 1H), 3.05 (m,1H), 2.95 (m, 2H), 2.09-1.99 (m, 7H); MS (APCI+) m/z 418.9 (M+H).

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with159f (100 mg, 0.239 mmol), 104h (350 mg, 1.07 mmol), sodium carbonate(183 mg, 1.72 mmol), 1,4-dioxane (8 mL) and water (2 mL). This mixturewas degassed with nitrogen for 30 min.Tetrakis(tri-phenylphosphine)palladium (66 mg, 0.057 mmol) was added.After heating at 100° C. for 5 h, the reaction mixture was cooled toroom temperature and partitioned between water (40 mL) and methylenechloride (100 mL). The layers were separated, and the aqueous phase wasextracted with methylene chloride (2×50 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was dissolved in methanol (5mL), and potassium carbonate (500 mg, 3.62 mmol) was added. Afterstirring at room temperature for 2 h, the reaction mixture waspartitioned between water (20 mL) and methylene chloride (20 mL). Thelayers were separated, and the aqueous phase was extracted withmethylene chloride (2×20 mL). The organic extracts were combined, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by flash chromatography to afford 159in 10% yield (12 mg) as a light brown solid: mp>250° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.71 (d, 1H, J=2.0 Hz), 8.64 (s, 1H), 8.29(dd, 1H, J=6.0, 1.5 Hz), 7.53 (s, 1H), 7.45 (td, 1H, J=6.0, 1.5 Hz),7.31 (m, 3H), 4.75 (m, 1H), 4.32 (m, 2H), 4.02 (m, 2H), 3.88 (m, 2H),3.60 (s, 3H), 3.05 (m, 1H), 2.96 (m, 1H), 2.76 (t, 2H, J=5.5 Hz), 1.95(m, 2H), 1.86 (m, 2H); MS (ESI+) m/z 498.2 (M+H).

Example 1603-({4-[(2R)-1,4-Dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-5-[2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-1,2-dihydropyrazin-2-one160

Following Example 121b,2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (167 mg, 0.36 mmol),5-bromo-3-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-one160a (WO 2009/039397; 122 mg, 0.3 mmol), 1M sodium carbonate solution(0.9 mL, 0.9 mmol), tetrakis(triphenylphosphine)-palladium(0) (18 mg,0.015 mmol) and 1,2-dimethoxyethane (3 mL). Work-up and flash columnchromatography (silica, 60:35:5 methylene chloride/diethylether/methanol) afford a mixture of2-(5-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 160b and 160 as yellow oil. The mixture (0.3 mmol) wasdeprotected using a mixture of THF (1 mL), water (0.5 mL) andisopropanol (1 mL), and Lithium hydroxide monohydrate (80 mg, 1.90mmol). Work-up and flash column chromatography (silica, 60:35:5methylene chloride/diethylether/methanol) afford a 37% yield of compound160 (2 steps, 70 mg) as a white solid: MS (ESI+) m/z 622.4 (M+H).

Example 1612-(3-(5-(1-(2-Hydroxyethyl)-5-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one161 Example 161a5-Bromo-3-(1-(2-(tert-butyldimethylsilyloxy)ethyl)-5-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one161a

A solution of5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 112a(1.08 g, 3.8 mmol) in anhydrous DMF (10 mL) was treated with 60%dispersion of NaH in mineral oil (0.17 g, 4.3 mmol) while stirring undernitrogen. After effervescence the reaction was stirred for an additional30 min. At this time the reaction was treated with(2-bromoethoxy)(tert-butyl)dimethylsilane (15-1) (0.908 g, 3.8 mmol) andcontinued to stir under nitrogen for 10 hours. After reaction water (50mL) was added slowly and the mixture was filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified byflash column chromatography eluting with petroleum ether/ethyl acetateto afford 161a (1 g, 35%), which was used directly without furtherpurification. LCMS: (M+H)+443.

Example 161b2-(5-(1-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 161b

A mixture of 161a (750 mg, 1.7 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (882 mg, 1.9 mmol), CH₃COONa (309 mg, 3.8 mmol),PdCl₂(dppf) (153 mg, 0.19 mmol) and K₃PO₄ (1 g, 3.8 mmol) suspended inCH₃CN (30 mL) and H₂O (2 mL) was heated at 110° C. for 12 h under argonatmosphere. After reaction the mixture was evaporated and the residuewas purified by reverse phase Combi-flash eluting with 0.3% NH₄HCO₃ in1:4 water/CH₃CN to give 161b as a brown solid (210 mg, 18%). LCMS:[M+H]⁺ 699.

Example 161c2-(3-(5-(1-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one161c

A mixture of 161b (210 mg, 0.4 mmol) and LiOH (372 mg, 16 mmol) inisopropanol/THF (1:1, 10 mL) and water (3 mL) was stirred at 30° C. for2 h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (2×10 mL). The combined extract was concentratedunder reduced pressure and the residue was purified on prep-HPLC to161c. LCMS: [M+H]⁺ 657

A solution of 161c, camphorsulfonic acid (330 mg, 1.5 mmol) in methanol(30 mL) was stirred at room temperature for 3 h. After reaction methanolwas evaporated and the residue was purified by prep-HPLC to afford 161as a brown solid (63 mg, 29%, two steps). LCMS: [M+H]⁺543. ¹H NMR (500MHz, DMSO) δ 7.96 (m, 1H), 7.45 (m, 1H), 7.33 (m, 2H), 7.24 (m, 1H),6.51 (s, 1H), 5.87 (s, 1H), 4.86 (m, 1H), 4.77 (m, 1H), 4.36 (m, 2H),4.15 (m, 3H), 3.90 (m, 3H), 3.64 (m, 2H), 3.57 (s, 3H), 2.51 (m, 2H),2.46 (m, 2H), 2.19 (s, 3H), 1.79 (m, 4H).

Example 1622-(2-(Hydroxymethyl)-3-(1-methyl-5-(2-methylpyrimidin-4-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one162 Example 162a 2-Methylpyrimidin-4-amine 162a

In a pressure-resistant vessel made of stainless steel having an innervolume of 500 mL was charged with 3-methoxypropanenitrile (10 g, 120mmol), 1.1.1-trimethoxy-ethane (39 g, 324 mmol) and 40.0 g (560 mmol,24% by weight ammonia-methanol solution). The mixture was stirred at130° C. for 8 hours. After completion of the reaction, it was filteredand concentrated to give a yellow solid. The solid was washed with ethylacetate (50 mL), dried in vacuo to afford 162a (7.8 g, 60%). LCMS:[M+H]⁺ 110

Example 162b5-Bromo-1-methyl-3-(2-methylpyrimidin-4-ylamino)pyridin-2(1H)-one 162b

Following Example 148a, 2.0 g of 162a and 4.0 g of3,5-dibromo-1-methyl-pyridin-2(1H)-one were reacted to give 162b as ayellow solid (2.3 g, 50%). LCMS: [M+H]⁺ 357 ¹H NMR (500 MHz, DMSO) δ9.20 (s, 1H), 8.78 (s, 1H), 8.26 (d, J=4.5, 1H), 7.68 (s, 1H), 7.18 (d,J=4.5, 1H), 3.59 (s, 3H), 2.52 (s, 3H).

Example 162c2-(1-Methyl-5-(2-methylpyrimidin-4-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 162c

Following Example 148b, 464 mg of2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a and 443 mg of 162b were reacted to give 162c as a yellowsolid (386 mg, 70%). LCMS: [M+H]⁺ 553

Following Example 148 160 mg of 162c was hydrolyzed to give 162 as awhite solid (90 mg, 60%). LCMS: [M+H]⁺ 511. ¹H NMR (500 MHz, DMSO) δ9.04 (s, 1H), 8.87 (s, 1H), 8.21 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H),7.36 (0=6.5, 1H),7.12 (s, 1H), 6.52 (s, H), 4.85 (s, 1H), 4.40 (s, 1H),4.17-4.10 (m, 3H), 3.92 (m, 1H), 3.61 (s, 3H), 2.60 (m, 2H), 2.47 (m,2H), 2.42 (S, 3H), 1.80 (m, 2H), 1.69 (m, 2H).

Example 1632-(3-(5-(1-(2-Hydroxyethyl)-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one163 Example 163a5-Bromo-3-(1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one163a

A mixture of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-3-amine116b (1.2 g, 5 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.3 g, 5mmol), XantPhos (300 mg, 0.5 mmol), Pd₂(dba)₃ (460 mg, 0.5 mmol) andCs₂CO₃ (4 g, 2.5 mmol) in dioxane (30 mL) was heated in a sealed tube at120° C. for 2 h under nitrogen. After reaction the mixture was filteredand the filtrated was evaporated in vacuo to give a yellow solid, whichwas then washed with ethyl acetate (6 mL×3) to give 163a as a yellowsolid (0.80 g, 38%) and used without further purification. MS: (M+H)⁺427.

Example 163b2-(5-(1-(2-(tert-Butyldimethylsilyloxy)ethyl)-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 163b

A mixture of 163a (800 mg, 1.88 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (1.3 g, 2.82 mmol), sodium acetate (308 mg, 3.76 mmol),PdCl₂(dppf) (153 mg, 0.188 mmol) and K₃PO₄ (1 g, 3.76 mmol) suspended inCH₃CN (50 mL) and water (3 mL) was heated at 110° C. for 12 h underargon atmosphere. The mixture was then evaporated and the residue waspurified by reverse phase Combi-flash eluting with 0.3% NH₄HCO₃ in 1:5water/CH₃CN to give 163b as a brown solid (350 mg, 29%). MS: (M+H)⁺ 685

Example 163c2-(3-(5-(1-(2-(tert-Butyldimethylsilyloxy)ethyl)-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-163c

To a solution of 163b (460 mg, 0.67 mmol) in propan-2-ol (15 mL),tetrahydrofuran (15 mL), and water (5 mL) was added LiOH monohydrate(1.6 g, 67 mmol). The mixture was stirred at 30° C. for 2 h. It was thenevaporated and the residue was purified by reverse phase Combi-flasheluting with 0.3% NH₄HCO₃ in 1:4 water/CH₃CN to give 163c as a brownsolid (300 mg, 70%). MS: (M+H)⁺ 643

A solution of 163c (300 mg, 0.50 mmol), camphorsulfonic acid (330 mg,1.5 mmol) in methanol (30 mL) was stirred at room temperature for 3 h.It was then evaporated and the residue was purified by prep-HPLC toafford 163 as a brown solid (140 mg, 57%). MS: (M+H)⁺ 529. ¹H NMR (500MHz, MeOD) δ 1.79 (s, 2H), 1.89 (s, 2H), 2.54-2.56 (t, J=5.5 Hz, 2H),2.62-2.66 (m, 2H), 3.70 (s, 3H), 3.84-3.86 (t, J=5.5 Hz, 2H), 4.01-4.02(m, 1H), 4.09-4.11 (t, J=5.5 Hz, 2H), 4.17-4.22 (m, 3H), 4.49-4.57 (m,2H), 6.05-6.06 (d, 1H), 6.71 (s, 1H), 7.22-7.23 (d, 1H), 7.35-7.37 (d,1H), 7.40-7.42 (d, 1H), 7.48-7.51 (m, 2H), 7.94-7.95 (d, 1H).

Example 1645-[3-(5-{[5-(Azetidin-3-yl)-1H-pyrazol-3-yl]amino}-1-methyl-6-oxopyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one164 Example 164b tert-Butyl 3-(2-Cyanoacetyl)azetidine-1-carboxylate164b

Following Example 136a, 1-tert-butyl 3-ethyl azetidine-1,3-dicarboxylate164a was converted to 164b as a yellow oil (crude). LCMS: (M+H)⁺ 424. ¹HNMR (500 MHz, DMSO) δ 12.1 (dd, J=2, 1H), 8.38 (s, 1H), 8.04 (d, J=2.5,1H), 7.36 (s, J=2.5, 1H), 6.06 (d, J=2.5, 1H), 4.18 (s, 2H), 3.80 (m,1H), 3.49 (s, 3H), 1.39 (s, 9H).

Example 164c tert-Butyl3-(5-Amino-1H-pyrazol-3-yl)azetidine-1-carboxylate 164c

Following Example 136b, 164b was converted to 164c which was useddirectly in the next step without further purification.

Example 164d tert-Butyl5-Amino-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazole-1-carboxylate164d

Following Example 136c, 164c was converted to 164d in 26% yield.

Example 164e tert-Butyl3-(5-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-1H-pyrazol-3-yl)azetidine-1-carboxylate164e

Following Example 136d, 164d was converted to 164e in 50% yield.

Example 164e[2-(5-{[5-(Azetidin-3-yl)-1H-pyrazol-3-yl]tert-butoxycarbonylamino}-1-methyl-6-oxopyridin-3-yl)-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 164e

Following Example 136e, 164d and(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 112b were reacted to give 164e in 39% of yield.

Example 164f[2-(5-{[5-(Azetidin-3-yl)-1H-pyrazol-3-yl]amino}-1-methyl-6-oxopyridin-3-yl)-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 164f

To a solution of 164e (300 mg, 0.42 mmol) in dioxane (2 mL) at roomtemperature was added HCl/dioxane (4M, 6 mL) dropwise. The reactionmixture was stirred for 1 h. After the reaction was finished, it wasconcentrated to afford 164f (crude product) as a black solid, which wasused in the next step without purification. LCMS: (M+H)⁺ 617

Following Example 136, 164f was converted to 164 in 20% yield. LCMS:(M+H)⁺ 575. ¹H NMR (500 MHz, DMSO) δ 7.78 (s, 1H), 7.28 (d, J=1.5, 1H),7.223 (s, 1H), 7.21 (s, 1H), 6.21 (s, 1H), 4.50 (m, 2H), 4.14 (m, 1H),4.00 (m, 3H), 3.90 (m, 2H), 3.71 (s, 3H), 3.09 (m, 1H), 2.96 (m, 1H),2.86 (m, 2H), 2.60 (m, 2H), 1.88 (m, 4H).

Example 1652-(3-(5-(5-(Azetidin-3-yl)-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one165 Example 165a tert-Butyl3-(3-(5-(2-(Acetoxymethyl)-5-fluoro-3-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-1H-pyrazol-5-yl)azetidine-1-carboxylate165a

Following Example 164f, 164e and4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d were reacted to give 165a in 20% yield. LCMS: (M+H)⁺ 700

Example 165b2-(5-(5-(Azetidin-3-yl)-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 165b

Following Example 164g, 165a was converted to crude 165b which was useddirectly in the next step without further purification. LCMS: (M+H)⁺ 600

Following Example 164, 165b was converted to 165 in 40% (two steps).LCMS: (M+H)⁺ 558. ¹H NMR (500 MHz, DMSO) δ 7.78 (s, 1H), 7.28 (d, J=1.5,1H), 7.22 (s, 1H), 7.21 (s, 1H), 6.21 (s, 1H), 4.50 (m, 2H), 4.14 (m,1H), 4.00 (m, 3H), 3.90 (m, 2H), 3.71 (s, 3H), 3.09 (m, 1H), 2.96 (m,1H), 2.86 (m, 2H), 2.60 (m, 2H), 1.88 (m, 4H).

Example 1662-(2-(Hydroxymethyl)-3-(1-methyl-6-oxo-5-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one166 Example 166a tert-Butyl2-(5-(2-(Acetoxymethyl)-3-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate166a

To a microwave tube equipped with a stirring bar, tert-butyl2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate158c (300 mg, mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (352 mg, 0.758 mmol), Pd(PPh₃)₄ (39.8 mg, 0.035 mmol),Na₂CO₃ aqueous solution (1.0 N, 2.27 mL, 2.27 mmol), and1,2-dimethoxyethane (3.5 mL) were added. The mixture was reacted inmicrowave at 130° C. for 10 min. methylene chloride (200 mL) was addedand the resulting mixture was washed with water (30 mL×3), brine (30mL×1), dried over MgSO₄, filtered, and removed solvent in vacuo. Silicagel column chromatography (methanol:methylene chloride=5:95) gave 166a.

To a round-bottomed flask equipped with a stirring bar, 166a andmethylene chloride (10 mL) were added. The solution was cooled to 0° C.in an ice-water bath. TFA (1 mL) was added and the resulting solutionwas stirred overnight. All the volatiles were removed in vacuo, and tothe bottle THF (10 mL), i-PrOH (10 mL), H₂O (10 mL), LiOH H₂O (1.00 g)were added. The resulting mixture was stirred at RT for 1 hr. All thesolvent were removed in vacuo and the resulting residue was added tomethylene chloride (200 mL), the solution was washed with water (×30mL), brine (30 mL), dried over MgSO₄, filtered, and removed solvent invacuo. Silica gel column chromatography (methanol:methylenechloride=10:90) gave 166 as a light brown solid, 53 mg. MS (ESI+) m/z551.3 (M+H).

Example 16710-[2-(Hydroxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one167 Example 167a (E)-Ethyl3-(2-Chloro-4,4-dimethylcyclopent-1-enyl)acrylate 167a

The following two procedures were adapted from Organic Preparations andProcedures Int., 29(4):471-498. A 500-mL single neck round bottomedflask equipped with a magnetic stirrer and nitrogen inlet was chargedwith 2-chloro-4,4-dimethylcyclopent-1-enecarbaldehyde (38 g, 240 mmol)in benzene (240 mL). To the solution was added ethoxycarbonylmethylenetriphenylphosphorane (84 g, 240 mmol). The mixture was stirred for 14 h.After that time, the solvent was evaporated and the residue wastriturated with hexanes (2 L) to extract the product away from the PPh₃by-products. The organic layer was dried over sodium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyusing a 100% hexane—1:1 hexane/ethyl acetate gradient to afford a 37%yield (20 g) of 167a.

Example 167b Ethyl5,5-Dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate 167b

A 250-mL single neck round bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 167a (17 g, 74 mmol) in DMSO(100 mL). To the solution was added sodium azide (9.6 g, 150 mmol). Themixture was then heated to 75° C. and stirred for 8 h. After cooling tort, H₂O (100 mL) and CH₂Cl₂ (200 mL) were added and the organic layerwas separated. The aqueous layer was extracted with CH₂Cl₂ (50 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by columnchromatography using a 100% hexane—1:1 hexane/ethyl acetate gradient toafford a 37% yield (5.7 g) of 167b.

Example 167c Ethyl1-(Cyanomethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate167c

A 250-mL single neck round bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 167b (6.2 g, 30 mmol) in DMF(57 mL). To the solution was added NaH (80% dispersion in mineral oil,1.26 g, 42.1 mmol). The resulting mixture was stirred at rt for 90 min.After that time, bromoacetonitrile (2.94 mL, 42 mmol) was added. Themixture was stirred for 14 h. After that time, water (100 mL) and ethylacetate (200 mL) were added and the organic layer was separated. Theaqueous layer was extracted with ethyl acetate (2×50 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyto afford a 95% yield (7 g) of 167c.

Example 167d Ethyl1-(2-Aminoethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylatehydrochloride 167d

A 500-mL Parr reactor bottle was purged with nitrogen and charged with10% palladium on carbon (50% wet, 2.0 g dry weight), 167c (4.5 g, 18mmol), 12% hydrochloric acid (9.2 mL, 37 mmol), ethyl acetate (80 mL)and ethanol (52 mL). The bottle was attached to a Parr hydrogenator,evacuated, charged with hydrogen gas to a pressure of 50 psi and shakenfor 6 h. After this time, the hydrogen was evacuated, and nitrogen wascharged into the bottle. Celite 521 (10.0 g) was added, and the mixturewas filtered through a pad of Celite 521. The filter cake was washedwith ethanol (2×50 mL), and the combined filtrates were concentrated todryness under reduced pressure. The crude residue 167d was carried ontothe next step without further purification.

Example 167e4,4-Dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one167e

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was purged with nitrogen and charged withcrude 167d (˜18 mmol), sodium ethoxide (6.2 g, 92 mmol) and ethanol (120mL). The mixture was stirred at 55° C. over night. After that time, thereaction mixture was concentrated under reduced pressure and the residuewas partitioned between ethyl acetate (200 mL) and water (100 mL). Thesolution was filtered. The solid was washed with ethyl acetate (15 mL)to give 850 mg of 167e. The organic layer was separated, and the aqueouslayer was extracted with ethyl acetate (2×100 mL). The combined organiclayers were dried over sodium sulfate and concentrated under reducedpressure to near dryness. The solution was filtered and the solid (1.44g) was washed with ethyl acetate (15 mL). The combined solids were driedunder vacuum a afford 61% yield (2.3 g) of 167e.

Example 167f2-Bromo-6-(9-oxo-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-10-yl)benzylAcetate 167f

A microwave tube equipped with a magnetic stirrer was charged with 167e(301 mg, 1.47 mmol), 2,6-dibromobenzyl acetate 104g (1.1 g, 3.0 mmol),CuI (140 mg, 0.7 mmol) Cs₂CO₃ (961 mg, 3.0 mmol),N′,N′,N′,N′-tetramethylethylenediamine (0.22 mL, 1.5 mmol) and1,2-dimethoxyethane (4.1 mL). The mixture was heated in microwave to150° C. for 3 h. After this time, the mixture was filtered and theresulting solid was washed with 9:1 CH₂Cl₂/MeOH (50 mL). The combinedorganics were washed with brine (20 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography eluting with a gradient ofhexanes—ethyl acetate to afford a 32% yield (200 mg) of 167f.

Example 167g10-[2-(Acetoxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one167g

A microwave tube equipped with a magnetic stirrer was charged with1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one109c (210 mg, 0.64 mmol), 167f (140 mg, 0.3 mmol), 1,2-dimethoxyethane(4 mL) and 1M aqueous sodium carbonate (1 mL). After bubbling N₂ for 15min, Pd(PPh₃)₄ (18 mg, 0.02 mmol) was added. The mixture was heated inmicrowave to 130° C. for 25 min. After this time, ethyl acetate (5 mL)and water (5 mL) were added. The separated aqueous layer was extractedwith ethyl acetate (2×5 mL). The combined organics were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography eluting with a gradient of CH₂Cl₂—60:35:5 CH₂Cl₂:diethylether:methanol to afford a 53% yield (93 mg) of 167g.

A 25 mL round bottom flask with a magnetic stirrer was charged with 167g(93 mg, 0.17 mmol), lithium hydroxide (35 mg, 0.8 mmol), THF (0.8 mL),isopropanol (0.8 mL) and water (1.7 mL). The mixture stirred at rt for 1h. After this time, ethyl acetate (5 mL) and water (5 mL) were added.The separated aqueous layer was extracted with ethyl acetate (2×5 mL).The combined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography eluting with a gradient ofCH₂Cl₂—60:35:5 CH₂Cl₂:diethyl ether:methanol to afford a 76% yield (23mg) of 167. MS (ESI+) m/z 511.8 (M+H).

Example 1682-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-(1-methylazetidin-3-yl)-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one168 Example 168a3-(5-(Azetidin-3-yl)-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one168a

To solution of tert-butyl3-(3-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-1H-pyrazol-5-yl)azetidine-1-carboxylate164e (1 g, 2.36 mmol) in dioxane (10 ml) at room temperature, was addedHCl/dioxane (4M, 20 mL) dropwise. Then the reaction mixture was stirredfor 1 h at room temperature. After the reaction was finished, it wasconcentrated to afford 168a as a yellow solid, which was used in thenext step without purification. LCMS: (M+H)⁺ 325

Example 168b5-Bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)-1H-pyrazol-3-ylamino)pyridine-2(1H)-one168b

To a solution of3-(5-(azetidin-3-yl)-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one168a (crude, 2.36 mmol) in methanol (30 mL) and acetic acid (5 mL) at 0°C., was added CH₂O (30% wt in H₂O) (12 g, 120 mmol), followed by theaddition of NaBH₄ (1.8 g, 47.2 mmol) in small portions over the periodof 1 h at 0° C. After the reaction was finished, the mixture wasadjusted to pH>7 with 2N aq. NaOH. It was then extracted with methylenechloride (60 mL×3), dried over Na₂SO₄ and, concentrated to give a yellowsolid, which was further purified on flash column eluting with 50:1methylene chloride/methanol containing 0.5% triethylamine to afford 168bas a yellow solid (50%, two steps).

Example 168c2-(1-Methyl-5-(5-(1-methylazetidin-3-yl)-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 168c

Following Example 136e, 168b and2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a were reacted to give 168c in 20% yield.

Following Example 136, 168c was converted to 168 in 54% yield. LCMS:(M+H)⁺ 554. ¹H NMR (500 MHz, DMSO) δ 8.05 (s, 1H), 8.01 (s, 1H), 7.45(t, J=8, 1H), 7.31 (m, 2H), 7.24 (d, J=2.5, 1H), 6.50 (s, 1H), 6.02 (s,1H), 4.37 (m, 2H), 4.14 (m, 3H), 3.88 (m, 1H), 3.57 (s, 3H), 3.53 (m,2H), 3.50 (m, 2H), 3.03 (m, 2H), 2.61 (m, 2H), 2.47 (m, 3H), 2.23 (s,3H), 1.78 (m, 2H), 1.69 (m, 2H).

Example 1695-[2-(Hydroxymethyl)-3-[1-methyl-6-oxo-5-({4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}amino)-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one169 Example 169a{2-[1-Ethyl-6-oxo-5-({4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}amino)1,6-dihydropyridin-3-yl]-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl}methylAcetate 169a

A mixture of5-bromo-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methylpyridin-2(1H)-one110c (500 mg, 1.54 mmol),(2-{6-oxo-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 111a (750 mg, 1.56 mmol), PdCl₂(dppf) (170 mg, 0.23 mmol), K₃PO₄(150 mg), and sodium acetate (60 mg) in MeCN (25 mL) and water (5 mL)was heated at reflux for 2 h. The solvent was evaporated in vacuo andthe residue was purified on reverse phase Combi-flash to give 169a (369mg, 40%). MS: [M+H]⁺ 600.

A mixture of 169a (440 mg, 0.73 mmol) and LiOH hydrate (308 mg, 7.3mmol) in isopropanol (20 mL) and H₂O (4 mL) was stirred at 30° C. for 2h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (20 mL×2). The combined extracts were concentratedunder reduced pressure. And the residue was purified on pre-HPLC to give169 (104 mg, 26%). MS: [M+H]⁺ 558. ¹H NMR (500 MHz, CDCl3) δ 7.93 (s,1H), 7.46-7.39 (m, 3H), 7.31-7.24 (m, 3H), 5.73 (s, 1H), 4.78 (s, 2H),4.61 (d, J=11.5, 1H), 4.42-4.20 (m, 2H), 4.14-3.98 (m, 4H), 3.90-3.82(m, 1H), 3.69 (s, 3H), 3.04-2.80 (m, 4H), 2.60-2.46 (m, 2H), 1.94-1.82(m, 4H).

Example 1705-[2-(Hydroxymethyl)-3-[1-methyl-5-({5-[(morpholin-4-yl)carbonyl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one170 Example 170a (6-Aminopyridin-3-yl)(morpholino)methanone 170a

To a solution of morpholine (9.00 g, 103 mmol) in EtOH (400 mL) wasadded EDCI (10.0 g, 52.2 mmol), HOBt (7.00 g 51.8 mmol), and6-aminonicotinic acid (6.00 g, 43.4 mmol). After stirring for 18 h, theresulting suspension was filtered. The solid was triturated with amixture of MeOH (100 mL) and methylene chloride (100 mL) to afford 170aas a white solid (2.7 g, 30%). LCMS: (M+H)⁺ 208

Example 170b5-Bromo-1-methyl-3-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)pyridine-2(1H)-one170b

Following Example 136e, 170a and 3,5-dibromo-1-methylpyridin-2(1H)-onewere reacted to give 170b in 21% yield. LCMS: (M+H)⁺ 394. ¹H NMR (500MHz, MeOD) δ 8.84 (d, J=2.5, 1H), 8.42 (d, J=2, 1H), 7.72 (m, 1H), 7.42(d, J=2, 1H), 7.11 (d, J=8.5, 1H), 3.72 (m, 8H), 3.63 (s, 3H).

Example 170c{2-[1-Methyl-5-({5-[(morpholin-4-yl)carbonyl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl}methylAcetate 170c

Following Example 136e, 170b and(2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 111a were reacted to give 170c in 65% yield. LCMS: (M+H)⁺ 668

Following Example 148, 170c was converted to 170 in 71% yield. LCMS:(M+H)⁺ 626. ¹H NMR (500 MHz, DMSO) δ 8.95 (s, 1H), 8.72 (d, J=2, 1H),8.25 (d, J=2, 1H), 7.64 (dd, J=8.5, 1H), 7.45 (m, 2H), 7.35 (m, 3H),4.85 (t, J=4, 1H), 4.35 (m, 2H), 4.03 (m, 1H), 3.88 (m, 1H), 3.59 (m,7H), 3.49 (m, 4H), 2.98 (m, 1H), 2.85 (m, 1H), 2.77 (m, 2H), 2.54 (m,2H), 1.79 (m, 4H).

Example 1712-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one171 Example 171a2-(1-Methyl-5-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 171a

Following Example 136d,5-bromo-1-methyl-3-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)pyridin-2(1H)-one170a and2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a were reacted to give 171a in 27% yield. LCMS: (M+H)⁺ 651

Following Example 170, 171a was converted to 171 in 60% yield. LCMS:(M+H)⁺ 609. ¹H NMR (500 MHz, DMSO) δ 8.85 (d, J=2, 1H), 8.32 (d, J=1.5,1H), 7.71 (dd, J=8.5, 1H), 7.53 (m, 1H), 7.43 (m, 3H), 7.35 (m, 3H),7.11 (d, J=8, 1H), 6.72 (s, 1H), 4.56 (m, 2H), 4.21 (s, 3H), 4.03 (m,1H), 3.71 (m, 11H), 2.65 (m, 2H), 2.55 (m, 2H), 1.89 (m, 2H), 1.80 (m,1H).

Example 1722-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one172 Example 172a5-Bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridine-2(1H)-one172a

A mixture of3-(5-(azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one155n (469 mg, 1.4 mmol), 37% aqueous formaldehyde solution (4 g, 50mmol), NaBH₃CN (261 mg, 4.2 mmol), and 1M zinc chloride in1,2-diethoxyethane (4 mL, 4.2 mmol) and methanol (40 mL) was stirred for2 hours at room temperature. The mixture was added to water (20 mL) andextracted with methylene chloride (50 mL×3). The organic layers wereconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 10:1 methylene chloride/methanol to give172a as a yellow solid (0.3 g, 83%). MS: [M+H]⁺ 348.

Example 172b2-(1-Methyl-5-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 172b

A sealed tube was charged with the mixture of 172a (167 mg, 0.48 mmol),2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one114a (231 mg, 0.48 mmol), Pd(dppf)Cl₂ (39 mg, 0.048 mmol), and Na₂CO₃(101 mg, 0.96 mmol) in N,N-dimethylformamide (18 mL). The system wasevacuated and then refilled with N₂. And the reaction mixture was heatedat 150° C. under microwave irradiation for 1 h. Then, the mixture wascooled to room temperature and filtered. The filtrate was concentratedunder reduced pressure and the resulting residue was purified by columnchromatography eluting with 15:1 methylene chloride/methanol to give172b as a brown solid (140 mg, 50%). MS: [M+H]⁺ 606.

To a solution of 172b (150 mg, 0.25 mol) in THF/isopropyl acetate/H₂O (6mL/6 mL/2 mL) was added LiOH (346 mg, 14 mmol) while stirring at roomtemperature. This mixture was stirred for 2 h. Then, 20 mL of water wasadded and the mixture was extracted with ethyl acetate (60 mL×3). Thecombined organic layer was dried with Na₂SO₄ and concentrated to give ayellow solid, which was further purified by prep-HPLC to afford 172 as awhite solid (50 mg, 35%). MS: [M+H]⁺ 565. ¹H NMR (500 MHz, DMSO) δ 8.66(s, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 7.65 (d, J=8, 1H), 7.46 (m, 1H),7.31 (m, 4H), 6.51 (s, 1H), 4.84 (s, 1H), 4.33 (m, 2H), 4.13 (m, 3H),3.85 (m, 1H), 3.59 (s, 3H), 3.53 (m, 2H), 3.35 (m, 1H), 3.02 (m, 2H),2.60 (m, 2H), 2.46 (m, 2H), 2.23 (s, 3H), 1.77 (m, 4H).

Example 17310-[2-(hydroxymethyl)-3-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one173 Example 173a10-[2-(Acetoxymethyl)-3-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one173a

In a 10-mL glass vessel equipped with a magnetic stirring bar wereplaced1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one197e (210 mg, 0.49 mmol),10-[2-(acetoxymethyl)-3-bromophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one167f (143 mg, 0.33 mmol), Pd(PPh₃)₄ (30 mg, 0.0.26 mmol) in 2 N Na₂CO₃(2 mL) and 1,2-dimethoxyethane (5 mL). The vessel was sealed with aseptum and placed into the microwave cavity. After the reaction mixturewas stirred at 125° C. for 7 min., it was purified by flashchromatography (dichloromethane:methanol, 85:15) to give 26% (50 mg) of173a as a solid.

A 100-mL, single-necked, round-bottomed flask equipped with a magneticstirring bar was charged with 173a (50 mg, 0.077 mmol), LiOH.H₂O (20 mg,0.83 mmol), THF (2 mL), isopropanol (2 mL), and water (2 mL). After thereaction mixture was stirred at room temperature for 3 h, it waspartitioned between dichloromethane (5 mL) and water (5 mL), and theorganic phase was extracted with dichloromethane (3×5 mL). The combinedorganic phases were washed with water (5 mL×2) and brine (5 mL×1), dried(Na₂SO₄), and concentrated. The crude product was re-dissolved indichloromethane (3 mL). To this solution was added hexane (10 mL) andthe resulting precipitates were filtered to give 75% yield (35 mg) of173. MS(ESI⁺) m/z 608.4 (M+H).

Example 1742-(2-(hydroxymethyl)-3-(4-methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one174 Example 174a tert-Butyl6-(6-(2-(Acetoxymethyl)-3-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate174a

To a microwave tube equipped with a stirring bar, tert-butyl6-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate120a (300 mg, 0.689 mmol), 114a (352 mg, 0.758 mmol), Pd(PPh₃)₄ (39.8mg, 0.0345 mmol), Na₂CO₃ aqueous solution (1.0 N, 2.27 mL, 2.27 mmol),1,2-dimethoxyethane (3.5 mL) were added. The mixture was reacted inmicrowave at 130° C. for 10 min. methylene chloride (200 mL) was addedand the resulting mixture was washed with water (30 mL×3), brine (30mL×1), dried over MgSO₄, filtered, and removed solvent in vacuo. Silicagel column chromatography (methanol:methylene chloride=5:95) gave 174a.

To a round-bottomed flask equipped with a stirring bar, 174a andmethylene chloride (50 mL) were added. The solution was cooled to 0° C.in an ice-water bath. TFA (1 mL) was added and the resulting solutionwas stirred overnight. Removed all the volatiles in vacuo, and to thebottle THF (10 mL), isopropanol (10 mL), water (10 mL), LiOH monohydrate(1.00 g) were added. The resulting mixture was stirred at RT for 1 hr.The solvent was removed in vacuo and the resulting residue was added tomethylene chloride (200 mL), the solution was washed with water (3 30mL), brine (30 mL), dried over MgSO₄, filtered, and removed solvent invacuo. Silica gel column chromatography (methanol:methylenechloride=10:90) gave 174 as a yellow solid, 28 mg. MS (ESI+) m/z 551.4(M+H).

Example 17510-[2-(Hydroxymethyl)-3-(1-methyl-6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one175 Example 175a3-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one175a

A sealed tube equipped with a magnetic stirrer was charged with5-bromo-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methylpyridin-2(1H)-one(110c) (250 mg, 0.77 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (290 mg, 1.2mmol), potassium acetate (230 mg, 2.3 mmol) and 1,4-dioxane (5.5 mL).After bubbling nitrogen through the resulting suspension for 30 min,[1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) complexwith CH₂Cl₂ (Pd Cl₂dppf:CH₂Cl₂ (1:1), 63 mg, 0.08 mmol) was then added,and the reaction was stirred at 105° C. for 90 min. After this time, themixture was cooled to ambient temperature, partition between water (20mL) and ethyl acetate (20 mL). The separated aqueous layer was extractedwith yl acetate (2×10 mL). The combined organics were washed with brine(30 mL), dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting crude 175a was used in the next stepwithout further purification.

Example 175b10-[2-(Acetoxymethyl)-3-(1-methyl-6-oxo-5-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one175b

A microwave tube equipped with a magnetic stirrer was charged with 175a(120 mg, 0.31 mmol), 167f (130 mg, 0.3 mmol), 1,2-dimethoxyethane (4 mL)and 1M aqueous sodium carbonate (1 mL). After bubbling N₂ for 15 min,Pd(PPh₃)₄ (18 mg, 0.02 mmol) was added. The mixture was heated inmicrowave to 130° C. for 10 min. After this time, 1 acetate (5 mL) andwater (5 mL) were added. The separated aqueous layer was extracted with1 acetate (2×5 mL). The combined organics were washed with brine (10mL), dried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by column chromatographyeluting with a gradient of CH₂Cl₂—60:35:5 CH₂Cl₂:diethyl ether:methanolto afford a 74% yield (140 mg) of 175b

A 25 mL round bottom flask with a magnetic stirrer was charged with 175b(140 mg, 0.23 mmol), lithium hydroxide (49 mg, 1.2 mmol), THF (1.2 mL),i-PrOH (1.2 mL) and water (2.4 mL). The mixture stirred at rt for 90min. After this time, ethyl acetate (5 mL) and water (5 mL) were added.The separated aqueous layer was extracted with ethyl acetate (2×5 mL).The combined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography eluting with a gradient ofCH₂Cl₂—60:35:5 CH₂Cl₂:diethyl ether:methanol to afford a 79% yield (100mg) of 175. MS (ESI+) m/z 555.3 (M+H).

Example 1762-(2-(Hydroxymethyl)-3-(5-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one176 Example 176a 5-(Methoxymethyl)-1-methyl-3-nitro-1H-pyrazole 176a

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with CH₃OH (50 mL),5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole 156d (8.8 g, 40 mmol) andCH₃ONa (4.3 g, 80 mmol). The reaction mixture was heated at reflux for 2h. After this time the reaction was cooled to room temperature andconcentrated. The residue was partitioned between ethyl acetate (60 mL)and water (60 mL). The aqueous layer was separated and extracted withethyl acetate (50 mL×2). The organic layers were combined, washed withbrine (50 mL), and dried over sodium sulfate. The drying agent wasremoved by filtration and the filtrate was concentrated under reducedpressure to afford 176a as a yellow oil (6.1 g, 90%). LCMS: [M+H]⁺ 172.

Example 176b 5-(Methoxymethyl)-1-methyl-1H-pyrazol-3-amine 176b

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with 176a (4 g, 23 mmol), Pd/C (1 g) and C₂H₅OH (100mL). The mixture was hydrogenated at room temperature for 15 h. It wasthen filtered and the filtrate was concentrated under reduced pressureto afford 176b as a yellow oil (3.3 g, 99%), which was used in the nextstep without further purification. MS: [M+H]⁺ 142.

Example 176c5-Bromo-3-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one176c

Following Example 148a, 1.7 g of 176b and 3.2 g of3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 176c as ayellow solid (2.8 g, 70%). MS: [M+H]⁺ 327. ¹H NMR (500 MHz, CDCl3) δ7.86 (d, J=2.5, 1H), 7.38 (s, 1H), 6.88 (d, J=2.5, 1H), 5.86 (s, 1H),4.41 (s, 2H), 3.82 (s, 3H), 3.58 (s, 3H), 3.36 (s, 3H).

Example 176d2-(5-(5-(Methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 176d

Following Example 148b, 557 mg of2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a and 327 mg of5-bromo-3-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one176c were reacted to give 176d as a yellow solid (420 mg, 72%). LCMS:[M+H]⁺ 585

Following Example 148, 240 mg of 176d was converted to 176 as a whitesolid (133 mg, 60%). LCMS: [M+H]⁺ 542. ¹H NMR (500 MHz, CDCl3) δ 7.91(d, J=2, 1H), 7.43 (m, 3H), 7.30 (d, J=2, 1H), 7.23 (s, 1H), 6.85 (s,1H), 5.96 (s, 1H), 4.60 (d, J=6, 1H), 4.40 (m, 3H), 4.16 (m, 3H), 3.94(m, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.34 (s, 3H), 2.60 (m, 4H), 1.89(m, 2H), 1.78 (m, 2H).

Example 1775-[2-(Hydroxymethyl)-3-(5-{[5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one177 Example 177a[2-(5-{[5-(Methoxymethyl)-1-methyl-1H-pyrazol-3-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 177a

Following Example 176d, 327 mg of5-bromo-3-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one176b and 481 mg of 111a were reacted to give 177a as a yellow solid (420mg, 70%). LCMS: [M+H]⁺ 602

Following Example 176, 240 mg of 177a was converted to 177 as a whitesolid (112 mg, 50%). LCMS: [M+H]⁺ 560. ¹H NMR (500 MHz, CDCl3) δ 7.90(s, 1H), 7.44-7.38 (m, 3H), 7.30-7.24 (m, 2H), 5.94 (s, 1H), 4.62 (d,J=11.5, 1H), 4.37 (m, 3H), 4.26 (d, J=10.5, 1H), 4.05 (m, 1H), 3.87 (m,1H), 3.75 (s, 3H), 3.68 (s, 3H), 3.34 (s, 3H), 2.85 (m, 4H), 2.54 (s,2H), 1.89 (s, 5H).

Example 1782-(5-fluoro-2-(hydroxymethyl)-3-(5-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one178 Example 178a4-Fluoro-2-(5-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 178a

A sealed tube was charged with the mixture of4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (230 mg, 0.48 mmol),5-bromo-3-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one176c (156 mg, 0.48 mmol), Pd(dppf)Cl₂ (39 mg, 0.048 mmol), Na₂CO₃ (101mg, 0.96 mmol) in DMF (18 mL). The system was evacuated and thenrefilled with N₂. And the reaction mixture was heated at 110° C. for 2h. Then, the mixture was cooled to room temperature and filtered. Thefiltrate was concentrated under reduced pressure and the resultingresidue was purified by column chromatography eluting with 15:1methylene chloride/methanol to give 178a as a brown solid (160 mg, 53%).MS: [M+H]⁺ 603.

To a solution of 178a (160 mg, 0.27 mol) in THF/iPA/H₂O (6 mL/6 mL/2 mL)was added LiOH (346 mg, 14 mmol) while stirring at room temperature.This mixture was stirred for 2 h. Then, 20 mL water was added and themixture was extracted with ethyl acetate (60 mL×3). The combined organiclayer was dried with Na₂SO₄ and concentrated to give a yellow solid,which was further purified by prep-HPLC to afford 178 as a white solid(60 mg, 40%). LCMS: [M+H]⁺ 561. ¹H NMR (500 MHz, DMSO) δ 8.16 (s, 1H),7.99 (m, 1H), 7.32 (m, 2H), 7.18 (m, 1H), 6.52 (s, 1H), 6.11 (s, 1H),4.89 (m, 1H), 4.38 (m, 2H), 4.31 (m, 2H), 4.17 (m, 3H), 3.90 (m, 1H),3.64 (s, 3H), 3.57 (s, 3H), 3.26 (s, 3H), 2.63 (m, 2H), 2.51 (m, 2H),1.70 (m, 4H).

Example 1795-[2-(Hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylazetidin-3-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-6-one179 Example 179a[2-(1-Methyl-5-{[5-(1-methylazetidin-3-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 179a

Following Example 176d,5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridin-2(1H)-one172a and(2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 111a were reacted to give 179a in 55% yield. LCMS: (M+H)⁺ 624

Following Example 176, 179a was converted to 179 in 42% yield. LCMS:(M+H)⁺ 582. ¹H NMR (500 MHz, MEOD) δ 8.73 (s, 1H), 8.17 (s, 1H), 7.74(m, 1H), 7.51 (m, 1H), 7.40 (m, 3H), 7.10 (d, J=3.5, 1H), 4.55 (m, 2H),4.31 (m, 2H), 4.13 (m, 1H), 4.06 (s, 3H), 3.99 (m, 1H), 3.71 (s, 3H),3.05 (m, 1H), 2.94 (m, 6H), 2.59 (m, 2H), 1.89 (m, 4H).

Example 1806-[2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-2-methyl-4-[(5-{[methyl(propan-2-yl)amino]methyl}pyridine-2-yl)amino]-2,3-dihydropyridazin-3-one180 Example 180a Methyl6-(6-Chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinate180a

Following Example 186b, 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one103e (4.0 g, 17.9 mmol), 186a (2.7 g, 17.9 mmol), cesium carbonate (12.8g, 39.4 mmol), and Xantphos (880 mg, 8.5 mol %), dioxane (120 ml) andtris(dibenzylideneacetone)dipalladium(0) (820 mg, 5 mol %) were reactedto give 180a (3.0 g, 57% yield).

Example 180b6-Chloro-4-(5-(hydroxymethyl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one180b

Following Example 186c, 180a (3.0 g, 10.2 mmol), methylene chloride (100mL) and 1.0M DIBAL-H in methylene chloride (30.5 mL, 30.5 mmol) werereacted to give 180b (2.3 g, 86% yield).

Example 180c(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)methylmethanesulfonate 180c

Intermediate 180b was treated with methanesulfonyl chloride anddiisopropylethylamine in methylene chloride at 0° C. to give 180c.

Example 180d6-Chloro-4-(5-((isopropyl(methyl)amino)methyl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one180d

Following Example 186c, 180c and methylisopropylamine were reacted togive 180d.

Example 180e 2-(5-(5-((isopropyl(methyl)amino)methyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 180e

Following Example 179a, 180d (125 mg, 0.39 mmol), 114a (215 mg, 0.47mmol), 1N Na₂CO₃ (0.86 mL) and tetrakis(triphenyl-phosphine)palladium(0)(23 mg, 5 mol %) were reacted to give 180e (150 mg, 61% yield).

Following Example 179, 180e (150 mg, 0.24 mmol), 1N LiOH (1.2 mL), THF(2 mL) and isopropanol (2 mL) were reacted and the mixture was purifiedvia column chromatography, silica, methanol/methylene chloride to give180 (105 mg, 75% yield). MS (ESI+) m/z 582.5 (M+H).

Example 1815-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one181 Example 181a5-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(acetoxymethyl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one181a

To a microwave tube equipped with a stirring bar,5-bromo-3-(5-(4-ethyl-piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one138c (250 mg, 0.637 mmol), boronic ester 111a (308 mg, 0.701 mmol),Pd(PPh₃)₄ (36.8 mg, 0.0319 mmol), Na₂CO₃ aqueous solution (1.0 N, 2.10mL, 2.10 mmol), 1,2-dimethoxyethane (3.0 mL) were added. The mixture wasreacted in microwave at 130° C. for 10 min. methylene chloride (200 mL)was added and the resulting mixture was washed with water (3×30 mL),brine (30 mL×1), dried over MgSO₄, filtered, and removed solvent invacuo. Silica gel column chromatography (methanol:methylenechloride=5:95) gave 181a.

To a round-bottomed flask equipped with a stirring bar, 181a, THF (5mL), isopropanol (5 mL), water (5 mL), LiOH monohydrate (300 mg) wereadded. The resulting mixture was stirred at RT for 1 hr. Removed all thesolvent in vacuo and the resulting residue was added to methylenechloride (200 mL), the solution was washed with water (30 mL×3), brine(30 mL×1), dried over MgSO₄, filtered, and removed solvent in vacuo.Silica gel column chromatography (methanol:methylene chloride=10:90)gave 181 as a brick red solid, 101 mg, MS (ESI+) m/z 625.4 (M+H).

Example 1825-(3-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-1-methyl-3-(pyrimidin-4-ylamino)pyridin-2(1H)-one182 Example 182a tert-Butyl(2,6-dibromo-4-fluorobenzyloxy)dimethylsilane182a

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 197b (5.00 g, 17.6mmol), imidazole (6.00 g, 88.0 mmol) and methylene chloride (125 mL).tert-butyldimethylsilyl chloride (7.96 g, 52.8 mmol) was added, and thereaction mixture was stirred at room temperature for 16 h. After thistime, the reaction was diluted with water (100 mL) and methylenechloride (100 mL). The layers were separated, and the aqueous phase wasextracted with methylene chloride (100 mL). The organic extracts werecombined and dried over sodium sulfate. The drying agent was removed byfiltration, and the solvent was evaporated under reduced pressure. Theresulting residue was purified by flash chromatography to afford a 96%yield (6.75 g) of 182a as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ7.30 (d, 2H, J=8.0 Hz), 4.93 (s, 2H), 0.93 (s, 9H), 0.15 (s, 6H).

Example 182b2-(3-Bromo-2-((tert-butyldimethylsilyloxy)methyl)-5-fluorophenyl)-6-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridin-1(2H)-one182b

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 105h (400 mg, 1.81 mmol),182a (1.44 g, 3.62 mmol), cesium carbonate (1.18 g, 3.62 mmol),N,N′-dimethylethylenediamine (159 mg, 1.81 mmol) and 1,4-dioxane (15mL). After bubbling nitrogen through the resulting suspension for 30min, copper iodide (174 mg, 0.905 mmol) was added. A reflux condenserwas attached to the flask, and the reaction mixture was heated at 100°C. for 16 h. After this time, the mixture was cooled to room temperatureand filtered. The filtrate was diluted with ethyl acetate (100 mL) andwater (50 mL), and the layers were separated. The aqueous layer wasextracted with ethyl acetate (2×30 mL), and the combined organic layerswere washed with brine (100 mL) and dried over sodium sulfate. Thedrying agent was removed by filtration. The filtrate was concentratedunder reduced pressure, and the resulting residue was purified by flashcolumn chromatography to afford 182b in 57% yield (554 mg) as a whitesolid: mp 38-39° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.32 (dd, 1H, J=8.0, 2.5Hz), 7.00 (dd, 1H, J=8.0, 2.5 Hz), 4.74 (s, 2H), 3.93 (m, 2H), 2.98 (m,1H), 2.80 (m, 1H), 2.77 (s, 2H), 2.52 (s, 2H), 1.28 (s, 3H), 1.27 (s,3H), 0.89 (s, 9H), 0.11 (s, 6H).

Example 182c2-((tert-Butyldimethylsilyloxy)methyl)-5-fluorophenyl-6-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridin-1(2H)-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-one182c

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 182b (554 mg, 1.03 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (785 mg, 3.09mmol), potassium acetate (404 mg, 4.12 mmol) and 1,4-dioxane (8 mL).After bubbling nitrogen through the resulting suspension for 30 min,Pd(dppf)Cl₂.CH₂Cl₂ (75 mg, 0.103 mmol) was added. A reflux condenser wasattached to the flask, and the reaction mixture was heated at reflux for8 h. After this time, the mixture was diluted with ethyl acetate (100mL) and water (75 mL), and the layers were separated. The aqueous layerwas extracted with ethyl acetate (2×50 mL), and the combined organiclayers were washed with brine (100 mL) and dried over sodium sulfate.The drying agent was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by flash column chromatography to afford 182c in 91% yield (600mg) as a white solid: mp 41-42° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.52 (dd,1H, J=8.0, 2.5 Hz), 7.02 (dd, 1H, J=8.0, 2.5 Hz), 5.14 (d, 1H, J=10.5Hz), 5.70 (d, 1H, J=10.5 Hz), 3.93 (m, 2H), 2.98 (m, 1H), 2.80 (m, 1H),2.77 (s, 2H), 2.52 (s, 2H), 1.34 (s, 3H), 1.33 (s, 3H), 1.26 (s, 12H),0.84 (s, 9H), 0.04 (s, 6H).

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with182c (300 mg, 0.513 mmol), 109b (111 mg, 0.394 mmol), sodium carbonate(125 mg, 1.18 mmol), 1,4-dioxane (8 mL) and water (2 mL). This mixturewas degassed with nitrogen for 30 min.Tetrakis-(triphenylphosphine)palladium(0) (46 mg, 0.039 mmol) was added.After heating at reflux for 2 h, the reaction mixture was cooled to roomtemperature and partitioned between water (40 mL) and methylene chloride(100 mL). The layers were separated, and the aqueous phase was extractedwith methylene chloride (2×50 mL). The organic extracts were combined,dried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was dissolved in THF (3 mL), andtetrabutyl-ammonium fluoride trihydrate (372 mg, 1.18 mmol) was added.After stirring at room temperature for 2 h, the reaction mixture waspartitioned between water (20 mL) and methylene chloride (20 mL). Thelayers were separated, and the aqueous phase was extracted withmethylene chloride (2×20 mL). The organic extracts were combined, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by flash chromatography to afford 182in 41% yield (88 mg) as an off-white solid: mp>250° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 9.22 (s, 1H), 8.72 (d, 1H, J=2.0 Hz), 8.65 (s, 1H), 8.29 (d,1H, J=6.0 Hz), 7.57 (d, 1H, J=2.0 Hz), 7.34 (dd, 1H, J=8.5, 3.0 Hz),7.31 (d, 1H, J=6.0 Hz), 7.29 (dd, 1H, J=8.5, 3.0 Hz), 4.87 (m, 1H), 4.31(m, 2H), 4.04 (m, 1H), 3.84 (m, 1H), 3.60 (s, 3H), 3.03 (m, 1H), 2.89(m, 1H), 2.75 (s, 2H), 2.53 (m, 2H), 1.23 (s, 6H); MS (ESI+) m/z 546.2(M+H).

Example 1835-(3-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-2-(hydroxymethyl)phenyl)-1-methyl-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-ylamino)pyridin-2(1H)-one183

Following Example 184, reaction of 131a (300 mg, 0.606 mmol) with 110c(151 mg, 0.466 mmol) gave a 51% yield (129 mg) of 183 as an off-whitesolid: mp 167-168° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.95(d, 1H, J=2.0 Hz), 7.44 (t, 1H, J=8.0 Hz), 7.33 (dd, 1H, J=8.0, 1.0 Hz),7.29 (dd, 1H, J=8.0, 1.0 Hz), 7.23 (d, 1H, J=2.0 Hz), 5.92 (s, 1H), 4.81(m, 1H), 4.71 (s, 2H), 4.36 (m, 2H), 4.01 (m, 3H), 3.94 (m, 2H), 3.85(m, 1H), 3.57 (s, 3H), 3.02 (m, 1H), 2.86 (m, 1H), 2.75 (m, 2H), 2.53(m, 2H), 1.23 (s, 6H); MS (ESI+) m/z 572.3 (M+H).

Example 1845-(3-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-2-(hydroxymethyl)phenyl)-1-methyl-3-(pyridin-2-ylamino)pyridin-2(1H)-one184 Example 184a 5-Bromo-1-methyl-3-(pyridin-2-ylamino)pyridin-2(1H)-one184a

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer, nitrogen inlet and reflux condenser was charged with3,5-dibromo-1-methylpyridin-2(1H)-one (936 mg, 3.51 mmol),2-aminopyridine (300 mg, 3.19 mmol), cesium carbonate (3.11 g, 9.57mmol) and 1,4-dioxane (20 mL). After bubbling nitrogen through theresulting solution for 20 minutes, Xantphos (184 mg, 0.319 mmol) andtris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.160 mmol) wereadded, and the reaction mixture was heated at 100° C. for 3 h. Afterthis time, the reaction was cooled to room temperature, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography to afford a 42% yield (376 mg) of 184a as anoff-white solid: mp 153-154° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (s,1H), 8.69 (d, 1H, J=2.4 Hz), 8.26 (dd, 1H, J=5.4, 1.5 Hz), 7.61 (m, 1H),7.54 (d, 1H, J=2.4 Hz), 7.33 (d, 1H, J=5.4 Hz), 6.86 (m, 1H), 3.45 (s,3H).

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with131a (300 mg, 0.606 mmol), 184a (131 mg, 0.466 mmol), sodium carbonate(148 mg, 1.40 mmol), 1,4-dioxane (8 mL) and water (2 mL). This mixturewas degassed with nitrogen for 30 min.Tetrakis(triphenyl-phosphine)palladium (54 mg, 0.047 mmol) was added.After heating at 100° C. for 3 h, the reaction mixture was cooled toroom temperature and partitioned between water (40 mL) and methylenechloride (100 mL). The layers were separated, and the aqueous phase wasextracted with methylene chloride (2×50 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was dissolved in methanol (5mL), and potassium carbonate (500 mg, 3.62 mmol) was added. Afterstirring at room temperature for 2 h, the reaction mixture waspartitioned between water (20 mL) and methylene chloride (20 mL). Thelayers were separated, and the aqueous phase was extracted withmethylene chloride (2×20 mL). The organic extracts were combined, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by flash chromatography to afford 184in 49% yield (118 mg) as a white solid: mp 150-151° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 8.66 (d, 1H, J=2.0 Hz), 8.57 (m, 1H), 8.16 (dd, 1H, J=5.0,1.0 Hz), 7.57 (m, 1H), 7.45 (t, 1H, J=8.0 Hz), 7.38 (d, 1H, J=2.0 Hz),7.36-7.31 (m, 2H), 7.28 (d, 1H, J=8.0 Hz), 6.78 (dd, 1H, J=11.0, 5.0Hz), 4.82 (m, 1H), 4.35 (m, 2H), 4.02 (m, 1H), 3.86 (m, 1H), 3.59 (s,3H), 3.01 (m, 1H), 2.87 (m, 1H), 2.75 (s, 2H), 2.53 (m, 2H), 1.23 (s,6H); MS (ESI+) m/z 527.2 (M+H).

Example 1855-(3-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-2-(hydroxymethyl)phenyl)-1-methyl-3-(1,5-dimethyl-1H-pyrazol-4-ylamino)pyridin-2(1H)-one185

Using the same general procedure as described for the preparation of184, reaction of 131a (300 mg, 0.606 mmol) with 142a (138 mg, 0.466mmol) gave a 41% yield (104 mg) of 185 as a yellow solid: mp 164-165°C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.93-7.92 (m, 2H), 7.44 (t, 1H, J=7.5Hz), 7.33 (dd, 1H, J=7.5, 1.0 Hz), 7.29 (dd, 1H, J=7.5, 1.0 Hz), 7.21(d, 1H, J=2.0 Hz), 5.88 (s, 1H), 4.83 (m, 1H), 4.36 (m, 2H), 4.02 (m,1H), 3.87 (m, 1H), 3.57 (s, 3H), 3.56 (s, 3H), 3.03 (m, 1H), 2.86 (m,1H), 2.75 (m, 2H), 2.53 (m, 2H), 2.17 (s, 3H), 1.23 (s, 6H); MS (ESI+)m/z 544.2 (M+H).

Example 1862-(2-(Hydroxymethyl)-3-(5-(5-((isopropyl(methyl)amino)methyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one186 Example 186a Methyl6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)nicotinate 186a

In a 300 mL sealed tube was placed 3,5-dibromo-1-methylpyridin-2(1H)-one(4.0 g, 15.0 mmol), methyl 6-aminonicotinate (2.3 g, 15.0 mmol), cesiumcarbonate (10.7 g, 33 mmol), and Xantphos (740 mg, 8.5 mol %). The flaskwas evacuated and filled with nitrogen 3×. Dioxane (100 ml) was addedand the mixture degassed for 25 min with bubbling nitrogen.Tris(dibenzylideneacetone)dipalladium(0) (690 mg, 5 mol %) was thenadded, the vessel sealed and the reaction heated to 120° C. overnight.The reaction was cooled and diluted with Ethyl acetate (500 mL) andsaturated aqueous NaHCO₃ (150 mL), the layers were separated andextracted ethyl acetate 2×. The organics were washed with brine 3×,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by chromatography: ISCO 80 g silica, ethylacetate/hexanes, to give 186a.

Example 186b5-bromo-3-(5-(hydroxymethyl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one186b

In a flask under N₂, 186a (500 mg, 1.5 mmol) was suspended in methylenechloride and cooled to −78° C. in a dry ice/acetone bath. 1.0M DIBAL-Hin methylene chloride (4.4 mL, 4.4 mmol) was slowly added via syringe.After the addition was complete the reaction was allowed to warm to −20°C. at which time the dry ice/acetone bath was exchanged for a ice/waterbath and the reaction stirred an additional 0.5 hr at which time it wasslowly quenched with 1N HCl (˜5 mL). The reaction was then diluted withethyl acetate and allowed to stir and warm to room temp over ˜1 hr. ThepH was adjusted to ˜7 with 1N NaOH and 50 mL of saturated aqueousRochelle's salt was added and the mixture heated and stirred at 40° C.for 1 hr during which time the mixture cleared. The layers wereseparated, the organics washed with brine, dried over Na₂SO₄, filteredand concentrated to give 186b as a white solid (420 mg, 90% yield).

Example 186d5-Bromo-3-(5-((isopropyl(methyl)amino)methyl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one186d

In a flask under N₂, 186b (350 mg, 1.13 mmol) was suspended in methylenechloride (20 mL) then di-isopropylethylamine (0.89 mL, 5.09 mmol) wasadded and the reaction cooled to 0° C. in an ice/water bath.Methanesulfonyl chloride (518 mg, 0.35 mL, 4.52 mmol) was added and thereaction allowed to warm to room temp and stir for ˜1 hr. The reactionwas diluted with methylene chloride and saturated aqueous sodiumbicarbonate was added. The layers were separated and the organics againwashed with bicarb then dried over anh. magnesium sulfate, filtered andconcentrated to give the mesylate 186c which was used directly toproduce 186d by dissolving 186c in DMF (10 mL) and transferring thesolution to a pressure flask whereupon N-methylpropan-2-amine (1.2 mL,830 mg, 11.3 mmol) was added, the flask sealed, and heated to 80° C.overnight. The reaction was allowed to cool then diluted with ethylacetate and water and the layers separated. The organics were washedwith brine 4×, dried over Na₂SO₄, filtered and concentrated to give186d.

Example 186f2-(5-(5-((Isopropyl(methyl)amino)methyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 186f

Step 1

In a pressure flask was placed 186d (205 mg, 0.56 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (213 mg,0.84 mmol), potassium acetate (220 mg, 2.24 mmol) and1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloridedichloromethane complex (817 mg, 0.1 mol %). The flask was evacuated andfilled with N₂ 3×, dioxane (5 mL) was added, the vessel sealed andheated to 90° C. for ˜3 hrs. The reaction was allowed to cool thendiluted with ethyl acetate, and filtered through a pad of celite andconcentrated under reduced pressure to give 186e which was used directlyin the next step.

Step 2

186e was dissolved in DME (5 mL) and transferred to a pressure flaskcontaining 109a (187 mg, 0.45 mmol), 1N Na₂CO₃ (1.2 ml) andtetrakis(tripheny-phosphine)palladium(0) (32 mg, 5 mol %). The flask wassealed and heated to 100° C. overnight. The reaction was then dilutedwith ethyl acetate and water, separated, washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by chromatography: ISCO 12 g silica, eluting with methanoland CH₂Cl₂, to give 186f (110 mg, 32% yield over 2 steps).

Following Example 119, 186f (110 mg, 0.18 mmol), 1N LiOH (0.88 mL), THF(2 mL) and isopropanol (2 mL) were reacted and purified via columnchromatography, ISCO 12 g silica, methanol/methylene chloride to give186 (80 mg, 77% yield). MS (ESI+) m/z 581.4 (M+H).

Example 1872-(2-(Hydroxymethyl)-3-(5-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one187 Example 187a6-Chloro-4-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one187a

A mixture of 5-(methoxymethyl)-1-methyl-1H-pyrazol-3-amine 176b (600 mg,4.26 mmol), XantPhos (300 mg, 0.51 mmol), Pd₂dba₃ (310 mg, 0.34 mmol),4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (103e) (1.22 g, 5.53 mmol)and Cs₂CO₃ (4.2 g. 12.8 mmol) in 1,4-dioxane (40 mL) was heated atreflux for 2 h. After the completion of the reaction, the mixture wasfiltered off and washed with methanol (100 mL). The filtrate wasevaporated in vacuo and the residue was purified on reverse phaseCombi-flash to give 187a (1.13 g, 94%). MS: [M+H]⁺ 284.

Example 187b2-(5-(5-(Methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 187b

A mixture of6-chloro-4-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one187a (300 mg, 1.06 mmol),2-(acetoxy-methyl)-3-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)phenylboronicacid 114a (500 mg, 1.3 mmol), PdCl₂(dppf) (116 mg, 0.16 mmol), K₃PO₄(100 mg), and NaOAc (50 mg) in MeCN (15 mL) and water (3 mL) was heatedat reflux for 2 h. The solvent was evaporated in vacuo and the residuewas purified on reverse phase Combi-flash to 187b (310 mg, 50%). MS:[M+H]⁺ 586.

A mixture of 187b (310 mg, 0.53 mmol) and LiOH hydrate (222 mg, 5.3mmol) in isopropanol (20 mL) and water (4 mL) was stirred at 30° C. for2 h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (20 mL×2). The combined extracts were concentratedunder reduced pressure. The residue was purified on prep-HPLC to give187 (103 mg, 36%). MS: [M+H]⁺ 544. ¹H NMR (500 MHz, DMSO) δ 9.25 (s,1H), 7.89 (s, 1H), 7.50-7.47 (m, 1H), 7.42-7.38 (m, 2H), 6.51 (s, 1H),6.22 (s, 1H), 4.63-4.60 (m, 1H), 4.48-4.45 (m, 1H), 4.40-4.35 (m, 3H),4.20-4.05 (m, 3H), 3.90-3.86 (m, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 3.26(s, 3H), 2.65-2.54 (m, 2H), 2.48-2.42 (m, 2H), 1.84-1.74 (m, 2H),1.74-1.64 (m, 2H).

Example 1882-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridine-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one188 Example 188a tert-Butyl4-(6-Nitropyridin-3-yl)piperazine-1-carboxylate 188a

Into a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1L) were added K₂CO₃ (40 g, 296 mmol) and tert-butylpiperazine-1-carboxylate (28 g, 148 mmol). The mixture was stirred at 65degree for overnight. After cooling down, it was poured into water (2L). The solid precipitated was collected and dried under vacuum. It wasthen further purified by flash column eluting with 20:1 petroleumether/ethyl acetate and then with methylene chloride to give 188a as ayellow solid (17 g, 37%). MS: [M+H]⁺ 309.

Example 188b tert-Butyl 4-(6-Aminopyridin-3-yl)piperazine-1-carboxylate188b

A 500-mL bottle was purged with nitrogen and charged with 188a (3.1 g,10 mmol), 10% palladium on carbon (50% wet, 1.0 g) and ethanol (100 mL).It was evacuated, charged with hydrogen gas, and stirred for 16 h atroom temperature. The hydrogen was then evacuated and nitrogen wascharged into the bottle. The catalyst was removed by filtration througha pad of Celite and the filtrate concentrated under reduced pressure toafford 188b (2.7 g, 97%). MS: [M+H]⁺ 279

Example 188c tert-Butyl4-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridine-3-yl)piperazine-1-carboxylate188c

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 188b(1.3 g, 4.7 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.24 g, 4.7mmol), and cesium carbonate (3.8 g, 12 mmol). After bubbling nitrogenthrough the resulting mixture for 30 minutes, XantPhos (272 mg, 0.47mmol) and tris(dibenzylideneacetone)dipalladium(0) (430 mg, 0.47 mmol)were added, and the reaction mixture was heated at reflux for 3 h. Afterthis time the reaction was cooled to room temperature, partitionedbetween ethyl acetate (100 mL) and water (100 mL), and filtered. Theaqueous layer was separated and extracted with ethyl acetate (50 mL×2).The organic layers were combined, washed with brine (50 mL), and driedover sodium sulfate. The drying agent was removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified on flash column eluting with 50:1 methylene chloride/methanolto afford 188c (1.3 g, 59%). MS: [M+H]⁺ 464.

Example 188d5-Bromo-1-methyl-3-(5-(piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one188d

A mixture of 188c (3.6 g, 7.8 mmol) and 4.0 M HCl/dioxane (10 mL) wasstirred for 5 h at room temperature. It was then concentrated at reducedpressure. The residue was basified with aqueous 1.0M NaOH and extractedwith methylene chloride. The combined organic layers were washed withwater and concentrated under reduced pressure to give 188d (2.46 g,87%). MS: [M+H]⁺ 364.

Example 188e5-Bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one188e

A mixture of 188d (2.75 g, 7.5 mmol), oxetan-3-one (1.6 g, 22.7 mmol),NaBH₃CN (4.75 g, 22.5 mmol), and zinc chloride (3 g, 22.7 mmol) inmethanol (125 mL) was stirred for 5 hours at 50 degree. The mixture wasadded to water and extracted with methylene chloride for three times.The organic layers were concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 25:1 methylenechloride/methanol to give 188e (1.92 g, 61%). MS: [M+H]⁺ 420. ¹H NMR(500 MHz, DMSO) δ 8.58 (d, J=2.5, 1H), 8.55 (s, 1H), 7.94 (d, J=3, 1H),7.54 (d, J=2.5, 1H), 7.39 (dd, J=3, 1H), 7.25 (d, J=4, 1H), 4.56 (t,J=6.5, 2H), 4.46 (t, J=6.5, 2H), 3.50 (s, 3H), 3.43 (m, 1H), 3.01 (m,4H), 2.40 (m, 4H).

Example 188f2-(1-Methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 188f

Following Example 148b, 464 mg of2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a and 420 mg of 188e were reacted to give 188f as a yellowsolid (360 mg, 54%). LCMS: [M+H]⁺ 678

Following Example 148, 270 mg of 188f was converted to 188 as a whitesolid (144 mg, 54%). LCMS: [M+H]⁺ 635. ¹H NMR (500 MHz, CDCl3) δ: 8.55(d, J=2.5, 1H), 7.89 (d, J=3, 1H), 7.80 (s, 1H), 7.47-7.41 (m, 3H),7.26-7.21 (m, 2H), 6.85 (s, 1H), 6.83 (d, J=8.5, 1H), 4.72-4.65 (m, 3H),4.59 (d, J=10.5, 1H), 4.43-4.36 (m, 2H), 4.20-4.13 (m, 3H), 3.93-3.89(m, 1H), 3.59-3.57 (m, 1H), 3.15 (s, 3H), 3.05 (m, 1H), 2.6-2.51 (m,7H), 1.89 (s, 2H), 1.78 (S, 2H).

Example 18910-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo-[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one189 Example 189a2-Bromo-4-fluoro-6-(9-oxo-4,4-dimethyl-1,10diazatricyclo[6.4.0.0^(2,6)]-dodeca-2(6),7-dien-10-yl)benzylAcetate 189a

A sealed tube was equipped with a magnetic stirrer and charged with 167e(740 mg, 3.6 mmol), 2,6-dibromo-4-fluorobenzyl acetate 197c (2.4 g, 7.2mmol) and cesium carbonate (2.6 g, 7.9 mmol) in 1,4-dioxane (36 mL).After bubbling nitrogen through the solution for 30 min, Xantphos (250mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium(0) (260 mg,0.29 mmol) were added, and the reaction mixture was heated to 100° C.for 16 h. After this time, H₂O (50 mL) and ethyl acetate (50 mL) wereadded. The aqueous layer was separated and extracted with ethyl acetate(2×50 mL). The combined organic extracts were washed with brine (100 mL)and dried over sodium sulfate. The resulting residue was purified bycolumn chromatography eluting with a gradient of 100% hexanes—100% Ethylacetate to afford a 56% yield (910 mg) of 189a.

Example 189b10-[5-Fluoro-2-(acetoxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one189b

A microwave tube equipped with a magnetic stirrer was charged with1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one109c (170 mg, 0.5 mmol), 189a (150 mg, 0.33 mmol), 1,2-dimethoxyethane(4 mL) and 1M aqueous sodium carbonate (1 mL). After bubbling N₂ for 15min, Pd(PPh₃)₄ (19 mg, 0.02 mmol) was added. The mixture was heated inmicrowave to 130° C. for 10 min. After this time, Ethyl acetate (5 mL)and water (5 mL) were added. The separated aqueous layer was extractedwith ethyl acetate (2×5 mL). The combined organics were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography eluting with a gradient of CH₂Cl₂—60:35:5 methylenechloride:diethyl ether:methanol to afford a 37% yield (71 mg) of 189b.

A 25 mL round bottom flask with a magnetic stirrer was charged with 189b(71 mg, 0.12 mmol), lithium hydroxide (26 mg, 0.6 mmol), THF (0.6 mL),isopropanol (0.6 mL) and water (1.2 mL). The mixture stirred at rt for 1h. After this time, ethyl acetate (5 mL) and water (5 mL) were added.The separated aqueous layer was extracted with ethyl acetate (2×5 mL).The combined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography eluting with a gradient ofC methylene chloride—60:35:5 CH₂Cl₂:diethyl ether:methanol to afford a58% yield (38 mg) of 189. MS (ESI+) m/z 529.7 (M+H).

Example 19010-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one190 Example 190a3-(5-(4-Ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one190a

To a round-bottomed flask equipped with a stirring bar,5-bromo-3-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one138c (305.6 mg, 0.696 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (185.4 g,0.730 mmol), Pd₂(dba)₃ (63.7 mg, 0.070 mmol), X-Phos (66.3 mg, 0.139mmol), KOAc (102.4 mg, 1.043 mmol), and dioxane (5 mL) were added. Themixture was heated at 90° C. for 4 hrs. The resulting mixture wasfiltered through celite, washed with ethyl acetate (200 mL). The organicphase was washed with water (50 mL), dried over MgSO₄, and removedsolvent in vacuo to yield the crude product 190a which was used directlyin the next step.

Example 190b10-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(acetoxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one190b

To a microwave tube equipped with a stirring bar, bromide 167f (150 mg,0.348 mmol), 190a (306 mg, 0.696 mmol), Pd(PPh₃)₄ (40.2 mg, 0.0348mmol), Na₂CO₃ aqueous solution (1.0 N, 1.15 mL, 1.15 mmol), DME (4 mL)were added. The mixture was reacted in microwave at 130° C. for 10 min.methylene chloride (200 mL) was added and the resulting mixture waswashed with water (3×30 mL), brine (30 mL×1), dried over MgSO₄,filtered, and removed solvent in vacuo. Silica gel column chromatography(methanol:methylene chloride=5:95) gave 190b.

To a round-bottomed flask equipped with a stirring bar, 190b, THF (3mL), isopropanol (3 mL), water (3 mL), LiOH monohydrate (200 mg) wereadded. The resulting mixture was stirred at RT for 1 hr. Removed all thesolvent in vacuo and the resulting residue was added to methylenechloride (200 mL), the solution was washed with water (3×30 mL), brine(30 mL), dried over MgSO₄, filtered, and removed solvent in vacuo.Silica gel column chromatography (MeOH:methylene chloride=10:90) gave190 as a yellow solid, 16 mg. MS (ESI+) m/z 622.5 (M+H).

Example 19110-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo-[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one191 Example 191a10-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one191a

A microwave tube equipped with a magnetic stirrer was charged with3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one150a (200 mg, 0.5 mmol), 189a (150 mg, 0.34 mmol), 1,2-dimethoxyethane(4 mL) and 1M aqueous sodium carbonate (1 mL). After bubbling N₂ for 15min, Pd(PPh₃)₄ (19 mg, 0.02 mmol) was added. The mixture was heated inmicrowave to 130° C. for 10 min. After this time, ethyl acetate (5 mL)and water (5 mL) were added. The separated aqueous layer was extractedwith ethyl acetate (2×5 mL). The combined organics were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography eluting with a gradient of methylene chloride—60:35:5CH₂Cl₂:diethyl ether:methanol to afford a 59% yield (125 mg) of 191a.

A 25 mL round bottom flask with a magnetic stirrer was charged with 191a(130 mg, 0.2 mmol), lithium hydroxide (43 mg, 1.0 mmol), THF (1 mL),isopropanol (1 mL) and water (2 mL). The mixture stirred at rt for 30min. After this time, ethyl acetate (5 mL) and water (5 mL) were added.The separated aqueous layer was extracted with ethyl acetate (2×5 mL).The combined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography eluting with a gradient ofmethylene chloride—60:35:5 CH₂Cl₂:diethyl ether:methanol to afford a 59%yield (68 mg) of 191. MS (ESI+) m/z 573.4 (M+H).

Example 1926-(3-(5-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-2,3-(5,5-dimethyl-5,6-dihydro-4H-cyclopenta)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one192

A 100-mL three-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 182c (300 mg, 0.513 mmol),110c (167 mg, 0.513 mmol), sodium carbonate (218 mg, 2.05 mmol), water(6 mL) and 1,4-dioxane (30 mL). After bubbling nitrogen through theresulting suspension for 20 min,tetrakis(triphenyl-phosphine)-palladium(0) (60.0 mg, 0.051 mmol) wasadded, and the reaction mixture was heated at 100° C. for 4 h. Afterthis time, the reaction mixture was cooled to room temperature andfiltered, and the filter cake was washed with a 1:10 mixture of methanoland methylene chloride (30 mL). The filtrate was concentrated underreduced pressure to afford a brown residue. Another 50-mL single-neckround-bottomed flask equipped with a magnetic stirrer and refluxcondenser was charged with the residue thus obtained, tetrabutylammoniumfluoride (1.0 M in THF, 2 mL, 2.00 mmol) and THF (6 mL). The mixture wasstirred at room temperature for 1.5 h. After this time, the reactionmixture was concentrated under reduced pressure. The resulting residuewas purified by flash chromatography to afford a 36% (110 mg) yield of192 as an off-white solid: mp 170-172° C.; ¹H NMR (500 MHz, DMSO-d₆) δ8.21 (s, 1H), 7.99 (d, 1H, J=2.0 Hz), 7.32 (dd, 1H, J=9.0, 3.0 Hz), 7.28(d, 1H, J=2.0 Hz), 7.15 (dd, 1H, J=9.0, 3.0 Hz), 5.93 (s, 1H), 4.86 (t,1H, J=5.0 Hz)

Example 1935-(2-(Hydroxymethyl)-3-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl))-1-methyl-3-(pyridin-3-ylamino)pyrazin-2(1H)-one193

Following Example 204, reaction of 111b (132 mg, 0.466 mmol) with 131a(300 mg, 0.606 mmol) afforded a 31% yield (75 mg) of 193 as an off-whitesolid: mp 135-136° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.53 (s, 1H), 9.15(d, 1H, J=1.9 Hz), 8.42 (m, 1H), 8.17 (dd, 1H, J=4.5, 1.4 Hz), 7.54 (dd,1H, J=7.4, 1.0 Hz), 7.47 (m, 2H), 7.34 (dd, 1H, J=8.0, 1.5 Hz), 7.30 (m,1H), 4.82 (m, 1H), 4.46 (m, 2H), 4.01 (m, 1H), 3.86 (m, 1H), 3.56 (s,3H), 3.02 (m, 1H), 2.88 (m, 1H), 2.75 (s, 2H), 2.54 (d, 2H, J=6.0 Hz),1.23 (s, 6H); MS (ESI+) m/z 528.2 (M+H).

Example 1945-(2-(Hydroxymethyl)-3-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one194

Following Example 204, reaction of 197e (176 mg, 0.466 mmol) with 131a(300 mg, 0.606 mmol) afforded a brown residue. A 100-mL single-neckround-bottomed flask equipped with a magnetic stirrer was charged withthe above crude residue, THF (8 mL), methanol (4 mL), water (4 mL) andlithium hydroxide monohydrate (196 mg, 4.66 mmol). The mixture wasstirred for 2 h at room temperature and then concentrated in vacuo. Theresidue was partitioned between a 20% (v/v) solution of methanol inmethylene chloride (150 mL) and water (30 mL). The organic layer wasseparated, and the aqueous layer was extracted with a 20% (v/v) solutionof methanol in methylene chloride (3×30 mL). The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography (silica, 0% to 10%methanol/methylene chloride) to afford a 33% yield (95 mg) of 194 as anoff-white solid: mp 142-143° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (d,1H, J=2.5 Hz), 8.33 (s, 1H), 7.85 (d, 1H, J=3.0 Hz), 7.45 (t, 1H, J=7.4Hz), 7.35 (m, 2H), 7.32 (m, 2H), 7.20 (d, 1H, J=9.3 Hz), 4.84 (m, 1H),4.32 (m, 2H), 4.03 (m, 1H), 3.85 (m, 1H), 3.58 (s, 3H), 3.03 (m, 5H),2.87 (m, 1H), 2.75 (s, 2H), 2.53 (m, 2H), 2.43 (m, 4H), 2.20 (s, 3H),1.23 (s, 6H); MS (ESI+) m/z 625.3 (M+H).

Example 1955-[2-(Hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino-[1,2-a]indol-2-yl}phenyl]-1-methyl-3-({5-[4-(propan-2-yl)piperazin-1-yl]pyridine-2-yl}amino)-1,2-dihydropyridin-2-one195

Following Example 138,5-bromo-1-methyl-3-(5-(4-(1-methylethyl)piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one220a was converted to 75 mg of 195 as a white solid. MS (ESI+) m/z 622(M+H).

Example 19610-(3-{5-[(1,5-Dimethyl-1H-pyrazol-3-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-5-fluoro-2-(hydroxymethyl)phenyl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one196 Example 196a3-(1,5-Dimethyl-1H-pyrazol-3-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one196a

A sealed tube equipped with a magnetic stirrer was charged with5-bromo-3-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one142a (380 mg, 1.4 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (690 mg, 2.7mmol), potassium acetate (401 mg, 4.1 mmol) and 1,4-dioxane (34 mL).After bubbling nitrogen through the resulting suspension for 30 min,[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complexwith methylene chloride (Pd Cl₂dppf:CH₂Cl₂ (1:1), 110 mg, 0.14 mmol) wasthen added, and the reaction was stirred at 105° C. for 16 h. After thistime, the mixture was cooled to ambient temperature, partition betweenwater (20 mL) and ethyl acetate (20 mL). The separated aqueous layer wasextracted with ethyl acetate (2×10 mL). The combined organics werewashed with brine (30 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting crude 196a was usedin the next step without further purification.

Example 196b10-(3-{5-[(1,5-Dimethyl-1H-pyrazol-3-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-5-fluoro-2-(acetoxymethyl)phenyl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one196b

A microwave tube equipped with a magnetic stirrer was charged with 196a(450 mg, 1.3 mmol), 189a (240 mg, 0.5 mmol), DME (4 mL) and 1M aqueoussodium carbonate (1.5 mL). After bubbling N2 for 15 min, Pd(PPh₃)₄ (31mg, 0.03 mmol) was added. The mixture was heated in microwave to 130° C.for 10 min. After this time, EtOAc (5 mL) and water (5 mL) were added.The separated aqueous layer was extracted with EtOAc (2×5 mL). Thecombined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography eluting with a gradient ofmethylene chloride—60:35:5 methylene chloride:diethyl ether:methanol toafford a 83% yield (260 mg) of 196b.

A 25 mL round bottom flask with a magnetic stirrer was charged with 196b(260 mg, 0.5 mmol), lithium hydroxide (94 mg, 2.2 mmol), THF (2 mL),isopropanol (2 mL) and water (5 mL). The mixture stirred at rt for 30min. After this time, ethyl acetate (5 mL) and water (5 mL) were added.The separated aqueous layer was extracted with ethyl acetate (2×5 mL).The combined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography using the Biotage KPNH12+M column eluting with a gradient of hexanes—ethyl acetate to afford a46% yield (110 mg) of 196. MS (ESI+) m/z 545.4 (M+H).

Example 1972-(5-fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one197 Example 197a 2,6-Dibromo-4-fluorobenzaldehyde 197a

A solution of 1,3-dibromo-5-fluoro-2-iodobenzene (50 g, 132 mmol) inanhydrous toluene (300 mL) cooled to −35° C. was added the solution ofisopropylmagnesium chloride (84 mL, 171 mmol, 2.0 M in diethyl ether)over a period of 30 minutes while maintaining the internal temperaturebelow −25° C. A clear brown solution was obtained. Stirring wascontinued for 1.5 h. Then anhydrous DMF (34 mL, 436 mmol) was added overa period of 30 minutes. The temperature of the reaction mixtureincreased to −19° C. The reaction mixture was warmed to 10° C. (roomtemperature) over 1 h and stirred at this temperature for 1.5 h. Thereaction was quenched with saturated aqueous NH₄Cl (100 mL), filteredand evaporated under reduced pressure. The residue was purified bysilica-gel column chromatography (eluting with petroleum ether/ethylacetate: from 50:1 to 20:1) to give 197a (20 g, yield 54%) as a yellowsolid.

Example 197b 2,6-Dibromo-4-fluorophenyl)methanol 197b

A solution of 197a (20 g, 71 mmol) in ethanol (500 mL) was added NaBH₄(10 g, 284 mmol). The mixture was stirred at room temperature (10° C.)for 4 h. TLC showed the start material disappeared. The reaction wasquenched with HCl solution (150 mL, 1 M). Most of ethanol was evaporatedat reduced pressure. The residue was extracted by ethyl acetate (3×500mL). The organic layers was combined and dried with anhydrous Na₂SO₄,evaporated in vacuo. The residue was purified by silica-gel columnchromatography (eluting with petroleum ether/ethyl acetate: from 50:1 to20:1) to give 197b (15 g, yield 75%) as a white solid.

Example 197c 2,6-Dibromo-4-fluorobenzyl acetate 197c

A 500-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 197b (23.0 g, 81.0 mmol),triethylamine (25.0 g, 247 mmol) in anhydrous methylene chloride (100mL). Acetic anhydride (10.0 g, 98.0 mmol) was added and this mixture wasstirred at room temperature for 16 h. After this time, the mixture wasdiluted with methylene chloride (100 mL) and washed with saturatedaqueous sodium bicarbonate (100 mL). The layers were separated and theaqueous layer was extracted with methylene chloride (2×20 mL). Theorganic extracts were combined and dried over sodium sulfate. The dryingagent was removed by filtration. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by flash columnchromatography (silica, 0% to 50% ethyl acetate/hexanes) to afford 197cin 87% yield (23.0 g) as a white solid.

Example 197d2-Bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 197d

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with ethyl1-(2-aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101k (3.8 g,20 mmol), 197c (20 g, 60 mmol), Xantphos (1.2 g, 2 mmol),tris(dibenzylideneacetone)dipalladium(0) (1.8 g, 2 mmol), Cs₂CO₃ (16 g,50 mmol), and 1,4-dioxane (120 mL). The system was evacuated and thenrefilled with N₂. A reflux condenser was attached to the flask, and thereaction mixture was heated at 100° C. for 16 h. It was then cooled toroom temperature and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by flash columnchromatography eluting with 5:1 petroleum ether/ethyl acetate to afford197d in 60% yield (5.2 g) as a white solid. MS: [M+H]⁺ 435. ¹H NMR (500MHz, DMSO) δ 7.70 (dd, J=3, 1H), 7.48 (dd, J=3, 1H), 6.52 (s, 1H), 5.01(m, 2H), 4.18 (m, 2H), 4.02 (m, 1H), 3.73 (m, 1H), 2.60 (m, 2H), 2.45(m, 2H), 1.98 (s, 3H), 1.77 (m, 2H), 1.68 (m, 2H).

Example 197f1-Methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one197f

A 1-L single-neck round-bottomed flask equipped with a magnetic stirrerand thermoregulator was purged with nitrogen and charged with 197e,prepared according to US 2009/0318448, (10.0 g, 0.027 mol),bis(pinacolato)diboron (8.06 g, 0.032 mol), potassium acetate (10.4 g,0.11 mol) and 1,4-dioxane (200 mL). After a stream of nitrogen waspassed through the resulting suspension for 30 min., Pd(dppf)Cl₂CH₂Cl₂(582 mg, 0.795 mmol) was added. The resulting reaction mixture wasstirred at reflux for 3 h. Then, it was cooled to room temperature,partitioned between water (400 mL) and ethyl acetate (600 mL) andfiltered through a pad of Celite. The organic phase was extracted, driedover sodium sulfate, filtered and concentrated. The residue wastriturated with a mixture of diethyl ether (50 mL) and hexanes (250 mL),and the suspension was filtered. The filter cake was dried under vacuumat room temperature to afford a 27% yield (3.04 g) of 197f as a brownsolid.

Example 197g4-Fluoro-2-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 197g

In a 10-mL glass vessel equipped with a magnetic stirring bar wereplaced 197f (244 mg, 0.58 mmol), 197d (200 mg, 0.46 mmol), Pd(PPh₃)₄ (33mg, 0.030 mmol) in 2 N Na₂CO₃ (1 mL) and DME (2 mL). The vessel wassealed with a septum and placed into the microwave cavity. After thereaction mixture was stirred at 125° C. for 7 min., it was purified byflash chromatography (dichloromethane:methanol, 85:15) to give 30% (90mg) of 197g as a solid.

A 100-mL, single-necked, round-bottomed flask equipped with a magneticstirring bar was charged with 197g (90 mg, 0.14 mmol), LiOH hydrate (60mg, 1.4 mmol), THF (2 mL), i-PrOH (2 mL), and water (2 mL). After thereaction mixture was stirred at room temperature for 3 h, it waspartitioned between dichloromethane (5 mL) and water (5 mL), and theorganic phase was extracted with dichloromethane (5 mL×3). The combinedorganic phases were washed with water (5 mL×2) and brine (5 mL×1), dried(Na₂SO₄), and concentrated. The crude product was re-dissolved indichloromethane (3 mL). To this solution was added hexane (10 mL) andthe resulting precipitates were filtered to give 81% yield (69 mg) of197. MS (ESI+) m/z 612.5 (M+H)

Example 19810-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one198 Example 198a 2,6-Dibromo-4-fluorobenzaldehyde 198a

A solution of 1,3-dibromo-5-fluoro-2-iodobenzene (50 g, 132 mmol) inanhydrous toluene (300 mL) cooled to −35° was added the solution ofisopropylmagnesium chloride (84 mL, 171 mmol, 2.0 M in Et₂O) over aperiod of 30 minute while maintaining the internal temperature below−25° (FIG. 6). A clear brown solution was obtained. Stirring wascontinued for 1.5 h. Then anhydrous DMF (34 mL, 436 mmol) was added overa period of 30 minutes. The temperature of the reaction mixtureincreased to −19°. The reaction mixture was warmed to 10° (roomtemperature) over 1 h and stirred at this temperature for 1.5 h. Thereaction was quenched with saturated aqueous NH₄Cl (100 mL), filteredand evaporated under reduced pressure. The residue was purified bysilica-gel column chromatography (eluting with petroleum ether/ethylacetate: from 50:1 to 20:1) to give 198a (20 g, yield 54%) as a yellowsolid.

Example 198b 2,6-Dibromo-4-fluorophenyl)methanol 198b

A solution of 198a (20 g, 71 mmol) in EtOH (500 mL) was added NaBH₄ (10g, 284 mmol). The mixture was stirred at room temperature (10° C.) for 4h. TLC showed the start material disappeared. The reaction was quenchedwith HCl solution (150 mL, 1 M). Most of EtOH was evaporated at reducedpressure. The residue was extracted by ethyl acetate (3×500 mL). Theorganic layers was combined and dried with anhy. Na₂SO₄, evaporated invacuo. The residue was purified by silica-gel column chromatography(eluting with petroleum ether/ethyl acetate: from 50:1 to 20:1) to give198b (15 g, yield 75%) as a white solid.

Example 198c 2,6-Dibromo-4-fluorobenzyl acetate 198c

A 500-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 198b (23.0 g, 81.0 mmol),triethylamine (25.0 g, 247 mmol) in anhydrous methylene chloride (100mL). Acetic anhydride (10.0 g, 98.0 mmol) was added and this mixture wasstirred at room temperature for 16 h. After this time, the mixture wasdiluted with methylene chloride (100 mL) and washed with saturatedaqueous sodium bicarbonate (100 mL). The layers were separated and theaqueous layer was extracted with methylene chloride (2×20 mL). Theorganic extracts were combined and dried over sodium sulfate. The dryingagent was removed by filtration. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by flash columnchromatography (silica, 0% to 50% ethyl acetate/hexanes) to afford 198cin 87% yield (23.0 g) as a white solid.

Example 198d2-Bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 198d

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with ethyl1-(2-aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101k (3.8 g,20 mmol), 198c (20 g, 60 mmol), Xantphos (1.2 g, 2 mmol),tris(dibenzylideneacetone)dipalladium(0) (1.8 g, 2 mmol), Cs₂CO₃ (16 g,50 mmol), and 1,4-dioxane (120 mL). The system was evacuated and thenrefilled with N₂. A reflux condenser was attached to the flask, and thereaction mixture was heated at 100° C. for 16 h. It was then cooled toroom temperature and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by flash columnchromatography eluting with 5:1 PE/EA to afford 198d in 60% yield (5.2g) as a white solid. MS: [M+H]⁺ 435. ¹H NMR (500 MHz, DMSO) δ 7.70 (dd,J=3, 1H), 7.48 (dd, J=3, 1H), 6.52 (s, 1H), 5.01 (m, 2H), 4.18 (m, 2H),4.02 (m, 1H), 3.73 (m, 1H), 2.60 (m, 2H), 2.45 (m, 2H), 1.98 (s, 3H),1.77 (m, 2H), 1.68 (m, 2H).

Example 198e5-bromo-1-methyl-3-[5-(4-methylpiperazin-1-yl)-pyridin-2-ylamino]-1H-pyridin-2-one198e

Step 1: 1-methyl-4-(6-nitropyridin-3-yl)piperazine

According to US 2009/0318448, into a solution of 5-bromo-2-nitropyridine(2.0 g, 9.85 mmol) in DMSO (10 mL) was added K2CO3 (2.72 g, 19.7 mmol)and 1-methylpiperazine (1.64 mL, 14.8 mmol), and tetrabutylammoniumiodide (36 mg). The mixture was stirred at 120 degree C. for overnight.It was allowed to cool down and acidified with 1N HCl. The mixture wasextracted with DCM. The aqueous layer was basified with saturatedNa2CO3, and further extracted with DCM. The combined organic layers weredried over Na2SO4 and concentrated to give a brown solid, which waswashed with small amount of water. The solid was dried under vacuum togive 2.16 g of 1-methyl-4-(6-nitropyridin-3-yl)piperazine (99% yield) asa yellow powder. LCMS: (M+H)⁺ 223

Step 2: 5-(4-methylpiperazin-1-yl)pyridin-2-amine

The suspension of 1-methyl-4-(6-nitropyridin-3-yl)piperazine (5 g, 22.5mmol), NH4Cl (12 g, 225 mmol), and Fe (5 g, 5 mmol) was stirred inEtOH/H2O (1:1) (100 mL) at 80° C. for 3 h. TLC showed starting material1-methyl-4-(6-nitropyridin-3-yl)piperazine disappeared. After filtrationon a pad of Celite, the solvent was removed under vacuum. EA and brinewere added into the mixture and the organic layer was separated, driedover Na2SO4 and concentrated at reduced pressure to give 2.5 g of5-(4-methylpiperazin-1-yl)pyridin-2-amine (yield 60%). LCMS: (M+H)⁺ 193.

Step 3

5-(4-methylpiperazin-1-yl)pyridin-2-amine (1 g, 10.5 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (1.87 g, 7 mmol), and Cs2CO3 (5 g,21 mmol) were added to dioxane (30 mL) in a sealed tube. After bubblingnitrogen through the resulting solution for 15 minutes, Xantphos (405mg, 0.7 mmol) and tris(dibenzylideneacetone)dipalladium(0) (320 mg, 0.35mmol) were added, and the reaction mixture was stirred at 100° C. for0.5 h. After filtration, the solid was washed by warm EA, and thefiltrate was concentrated to afford the crude product as a black solid.The crude product was the re-crystallized from MeOH to give 1.26 g (64%)of 198e. LCMS: (M+H)⁺ 380. ¹H NMR (500 MHz, DMSO) δ 8.57 (d, J=2.5, 1H),8.54 (s, 1H), 7.93 (d, J=3, 1H), 7.44 (d, J=2.5, 1H), 7.38 (dd, J=3.5,2H), 7.24 (d, J=4.5, 1H), 3.50 (s, 3H), 3.07 (m, 4H), 2.44 (m, 4H), 2.21(s, 3H).

Example 198f1-Methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one198f

A 1-L single-neck round-bottomed flask equipped with a magnetic stirrerand thermoregulator was purged with nitrogen and charged with 198e (10.0g, 0.027 mol), bis(pinacolato)diboron (8.06 g, 0.032 mol), potassiumacetate (10.4 g, 0.11 mol) and 1,4-dioxane (200 mL). After a stream ofnitrogen was passed through the resulting suspension for 30 min.,Pd(dppf)Cl₂CH₂Cl₂ (582 mg, 0.795 mmol) was added. The resulting reactionmixture was stirred at reflux for 3 h. Then, it was cooled to roomtemperature, partitioned between water (400 mL) and ethyl acetate (600mL) and filtered through a pad of Celite. The organic phase wasextracted, dried over sodium sulfate, filtered and concentrated. Theresidue was triturated with a mixture of diethyl ether (50 mL) andhexanes (250 mL), and the suspension was filtered. The filter cake wasdried under vacuum at room temperature to afford a 27% yield (3.04 g) of198f as brown solids.

Example 198g4-Fluoro-2-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 198g

In a 10-mL glass vessel equipped with a magnetic stirring bar wereplaced 198f (244 mg, 0.58 mmol), 198d (200 mg, 0.46 mmol), Pd(PPh₃)₄ (33mg, 0.030 mmol) in 2 N Na₂CO₃ (1 mL) and DME (2 mL). The vessel wassealed with a septum and placed into the microwave cavity. After thereaction mixture was stirred at 125° C. for 7 min., it was purified byflash chromatography (dichloromethane:MeOH, 85:15) to give 30% (90 mg)of 198g as solids.

Following Example 148, 198g was converted to 75 mg of 198 as a whitesolid. MS (ESI+) m/z 626.6 (M+H).

Example 1995-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-[(1-methylazetidin-3-yl)oxy]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one199 Example 199a tert-Butyl 3-Iodoazetidine-1-carboxylate 199a

A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (25-3) (3.5 g,0.02 mol) in toluene (200 mL) was treated with imidazole (4.08 g, 0.06mol), PPh₃ (0.6 g, 0.04 mol), and I₂ (7.62 g, 0.03 mol). The mixture washeated at 100° C. for 1 h and cooled down to room temperature. It wasthen poured into saturated NaHCO₃ solution (30 mL). Excess PPh₃ wasdestroyed by addition of iodine until I₂ coloration persisted in organiclayer. The mixture was washed with 5% Na₂SO₃ solution, dried overNa₂SO₄, and evaporated in vacuo. The residue was purified on silica gelcolumn to give 199a (5.31 g, 93%). MS: [M+H]⁺ 284.

Example 199b tert-Butyl3-(6-Nitropyridin-3-yloxy)azetidine-1-carboxylate 199b

A mixture of 199a (2.24 g, 7.9 mmol), 6-nitropyridin-3-ol (1 g, 7.2mmol) and Cs₂CO₃ (2.6 g, 7.9 mmol) in DMF (8 mL) was heated at 125° C.in a sealed tube for overnight. The mixture was filtered off and washedwith ethyl acetate (20 mL×2). The filtrate was evaporated in vacuo andthe residue was purified on reverse phase Combi-flash to give 199b (1.25g, 59%). MS: [M+H]⁺ 296.

Example 199c tert-Butyl3-(6-Aminopyridin-3-yloxy)azetidine-1-carboxylate 199c

A 100-mL Parr hydrogenation bottle was purged with nitrogen and chargedwith 199b (1.07 g, 3.6 mmol), 10% palladium on carbon (50% wet, 0.3 g)and methanol (60 mL). The bottle was evacuated, charged with hydrogengas to a pressure of 25 psi, and shaken for 2 h on a Parr hydrogenationapparatus. The hydrogen was then evacuated and nitrogen charged to thebottle. The catalyst was removed by filtration through a pad of Celiteand the filtrate was concentrated under reduced pressure to afford 199c(0.95 g, 99%). MS: [M+H]⁺ 266.

Example 199d tert-Butyl3-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yloxy)azetidine-1-carboxylate199d

A mixture of 199c (950 mg, 3.6 mmol), XantPhos (125 mg, 0.29 mmol),Pd₂dba₃ (260 mg, 0.29 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.03g, 3.9 mmol) and Cs₂CO₃ (1.8 g. 7.2 mmol) in 1,4-dioxane (20 mL) washeated at reflux for 2 h. After the completion of the reaction, themixture was filtered off and washed with methanol (100 mL). The filtratewas evaporated in vacuo. The residue was purified on reverse phaseCombi-flash to give 199d (1.46 g, 91%). MS: [M+H]⁺ 451.

Example 199e3-(5-(Azetidin-3-yloxy)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-onehydrochloride 199e

A mixture of 199d (1.46 g, 3.2 mmol) and HCl/1,4-dioxane (3.2 mL, 12.8mmol, 4 M) in methanol (20 mL) was heated at 80° C. for 1 h. The mixturewas concentrated under reduced pressure to give 199e (1.24 g, 99%). MS:[M+H]⁺ 351.

Example 199f5-Bromo-1-methyl-3-(5-(1-methylazetidin-3-yloxy)pyridin-2-ylamino)-pyridine-2(1H)-one199f

A mixture of 199e (1.24 g, 3.2 mmol), HCHO solution (15 mL, 37% inwater), acetic acid (1 mL) and NaBH(OAc)₃ (1.36 g, 6.4 mmol) in methanol(10 mL) was stirred at room temperature for 4 h. The solvent wasevaporated in vacuo and the residue was extracted with ethyl acetate (20mL×3). The combined extracts were dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified on reversephase Combi-flash to give 199f (940 mg, 80%). MS: [M+H]⁺ 365.

Example 199g{4-Fluoro-2-[1-methyl-5-({5-[(1-methylazetidin-3-yl)oxy]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-6-{6-oxo-8-thia-5azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}phenyl}methylAcetate 199g

A mixture of 199f (434 mg, 1.2 mmol),(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 212b (600 mg, 1.2 mmol), PdCl₂(dppf) (134 mg, 0.18 mmol), K₃PO₄(150 mg), and NaOAc (100 mg) in MeCN (8 mL) and water (2 mL) was heatedat 110° C. in a sealed tube for 2 h. The solvent was evaporated invacuo. The residue was purified on reverse phase Combi-flash to give199g (320 mg, 41%). MS: [M+H]⁺ 658.

A mixture of 199g (320 mg, 0.49 mmol) and LiOH hydrate (409 mg, 9.8mmol) in isopropanol (20 mL) and water (3 mL) was stirred at 30° C. for2 h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (20 mL×2). The combined extracts were concentratedunder reduced pressure. The residue was purified on prep-HPLC to give199 (30 mg, 10%). MS: [M+H]⁺ 616. ¹H NMR (500 MHz, CDCl3) δ 8.52 (d,J=2.0, 1H), 7.82 (s, 1H), 7.75 (d, J=2.5, 1H), 7.48 (d, J=2.0, 1H),7.16-7.14 (m, 1H), 7.11-7.09 (m, 1H), 6.98-6.96 (m, 1H), 6.79 (d, J=9.0,1H), 4.76-7.72 (m, 1H), 4.56 (d, J=11.5, 1H), 4.32-4.25 (m, 1H),4.19-4.07 (m, 2H), 3.97-3.80 (m, 3H), 3.69 (s, 3H), 3.23-3.15 (m, 2H),3.00-2.81 (m, 4H), 2.59-2.50 (m, 2H), 2.47 (s, 2H), 1.93-1.83 (m, 4H).

Example 2002-(3-(5-(5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one200 Example 200a 5-(Azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole200a

Following Example 156e, 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole156d (1.76 g, 8 mmol), azetidine (550 mg, 9.6 mmol),di-isopropylethylamine (1.75 mL, 10 mmol) and methylene chloride (40 mL)were stirred at room temperature for 3-5 h. Work-up and concentratedunder reduced pressure to afford5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole 200a (quant.) asyellow oil, which was used without further purification for the nextstep. MS (ESI+) m/z 197.1 (M+H).

Example 200b 5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-amine 200b

Following Example 156f, 10% palladium on carbon (30% wet, 480 mg dryweight) and a solution of 200a (1.6 g, 8 mmol) in ethanol (50 mL) werereacted. The reaction mixture was filtered through a pad of Celite 521.The filter cake was washed with ethanol (2×30 mL), and the combinedfiltrates were concentrated to dryness under reduced pressure to afford5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-amine 200b (quantitative)as yellow oil. MS (ESI+) m/z 167.1 (M+H).

Example 200c3-(5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one200c

Following Example 156g, 200b (350 mg, 2 mmol),3,5-dibromo-1-methyl-1H-pyridin-2-one (0.54 g, 2 mmol), cesium carbonate(1.3 g, 4 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.18 g, 0.2mmol), Xantphos (0.23 g, 0.4 mmol) and 1,4-dioxane (20 mL) were heatedat 100° C. for 8 hours. Work-up and flash column chromatography (silica,3:1 methylene chloride/methanol) give a 98% yield (0.69 g) of3-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one200c as a yellow solid. MS (ESI+) m/z 354.1 (M+H).

Example 200d2-(5-(5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 200d

Following Example 121b,4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (202 mg, 0.42 mmol),3-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one200c (105 mg, 0.3 mmol), 1M sodium carbonate solution (1.2 mL, 1.2mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) and1,2-Dimethoxyethane (3 mL) were heated at 130° C. for 10 minutes in themicrowave reactor. Work-up and the resulting residue was purified byflash column chromatography (silica, 3:1 methylene chloride/methanol) togive 180 mg compound 200d (quant., contain 3% 200) as a yellow residue:MS (ESI+) m/z 628.1 (M+H).

Intermediate 200d (0.3 mmol) was deprotected using Example 121, usingTHF (1 mL), water (0.5 mL), isopropanol (1 mL) and lithium hydroxidemonohydrate (80 mg, 1.93 mmol). Work-up and the resulting residue waspurified by flash column chromatography (NH-silica, ethylacetate/hexanes) to afford a 25% yield (two steps, 45 mg) of 200 as alight pink solid: MS (ESI+) m/z 586.6 (M+H).

Example 2012-(5-(5-(4-Ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAlcohol 201 Example 201b2-(5-(5-(4-Ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 201b

A 44-mL sealed tube equipped with a magnetic stirrer was charged with138e (190 mg, 0.49 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (200 mg, 0.79mmol), potassium acetate (190 mg, 2.0 mmol) and 1,4-dioxane (5 mL).After the mixture was degassed for 30 minutes, Pd(dppf)Cl₂.CH₂Cl₂ (40mg, 0.049 mmol) was added. The resulting reaction mixture was stirred at105° C. for 6 h. Then, it was cooled to room temperature and filteredthrough a pad of Celite. The filtrate was concentrated, and the crudeboronolate product was redissolved in DME (2 mL) and transferred into a10-mL microwave reaction vessel. To this solution was added2-bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 197d (171 mg, 0.39 mmol), Pd(PPh₃)₄ (30 mg, 0.025 mmol), and 2 NNa₂CO₃ (2 mL). Then, the reaction mixture was degassed for 5 minutes andplaced into the microwave cavity. After the reaction mixture was stirredat 125° C. for 7 min., it was purified by flash chromatography(dichloromethane:MeOH, 85:15) to give 46% (120 mg) of 201b as solids.

A 100-mL, single-necked, round-bottomed flask equipped with a magneticstirring bar was charged with2-(5-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 201b (120 mg, 0.18 mmol), LiOH.H₂O (80 mg, 1.8 mmol), THF (2mL), isopropanol (2 mL), and water (2 mL). After the reaction mixturewas stirred at room temperature for 3 h, it was partitioned betweendichloromethane (5 mL) and water (5 mL), and the organic phase wasextracted with dichloromethane (3×5 mL). The combined organic phaseswere washed with water 2×5 mL) and brine (5 mL), dried (Na₂SO₄), andconcentrated. The crude product was re-dissolved in dichloromethane (3mL). To this solution was added hexane (10 mL) and the resultingprecipitates were filtered to give 40% yield (45 mg) of 201; MS(ESI⁺)m/z 626.4 (M+H).

Example 2025-[5-fluoro-2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-3-{[5-(1-methylpyrrolidin-2-yl)pyridine-2-yl]amino}-1,2-dihydropyridin-2-one202 Example 202a5-Bromo-1-methyl-3-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)pyridin-2(1H)-one202a

Following Example 142a, 5-(1-methylpyrrolidin-2-yl)pyridin-2-amine (500mg, 2 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (0.54 g, 2 mmol),cesium carbonate (1.9 g, 6 mmol),tris(dibenzylidene-acetone)dipalladium(0) (0.18 g, 0.2 mmol), Xantphos(0.23 g, 0.4 mmol) and 1,4-dioxane (20 mL) were heated at 100° C. for 8hours. Work-up and flash column chromatography (silica, 9:1 methylenechloride/methanol) give a 82% yield (0.6 g) of5-bromo-1-methyl-3-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)pyridin-2(1H)-one202a as a green solid: MS (ESI+) m/z 365.0 (M+H).

Following Example 121b,4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (338 mg, 0.7 mmol), 202a (181 mg, 0.5 mmol), 1M sodiumcarbonate solution (2 mL, 2 mmol),tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and1,2-dimethoxyethane (5 mL) were reacted. Work-up and flash columnchromatography (silica, 3:1 methylene chloride/methanol) give a mixture(200 mg) of4-fluoro-2-(1-methyl-5-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate and 202 as a yellow residue.

The above residue was deprotected following Example 121, except using amixture of THF (1 mL), water (0.5 mL), isopropanol (1 mL) and lithiumhydroxide monohydrate (55 mg, 1.2 mmol). Work-up and flash columnchromatography (NH-silica, ethyl acetate/hexanes) give a 32% yield (60mg) of 202 as a yellow solid: MS (ESI+) m/z 597.4 (M+H).

Example 2035-(3-(6,6-Dimethyl-5,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-2-(hydroxymethyl)phenyl)-1-methyl-3-(pyrimidin-4-ylamino)pyridin-2(1H)-one203

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 105i (226 mg, 0.506 mmol),109c (200 mg, 0.610 mmol), sodium carbonate (160 mg, 1.51 mmol), water(2 mL) and 1,4-dioxane (8 mL). After bubbling nitrogen through theresulting suspension for 30 min,tetrakis(triphenyl-phosphine)palladium(0) (60 mg, 0.052 mmol) was added.A reflux condenser was attached to the flask, and the reaction mixturewas heated at 100° C. for 2 h. After this time, the mixture was dilutedwith 90:10 methylene chloride/methanol (100 mL) and water (75 mL), andthe layers were separated. The aqueous layer was extracted with 90:10methylene chloride/methanol (2×50 mL), and the combined organic layerswere washed with brine (100 mL) and dried over sodium sulfate. Thedrying agent was removed by filtration. The filtrate was concentratedunder reduced pressure, and the resulting residue was dissolved in amixture of THF (3 mL), water (3 mL) and methanol (3 mL). Lithiumhydroxide monohydrate (61 mg, 1.45 mmol) was added, and the reaction wasstirred at room temperature for 2 h. After this time, the mixture wasdiluted with 90:10 methylene chloride/methanol (100 mL) and water (50mL), and the layers were separated. The aqueous layer was extracted with90:10 methylene chloride/methanol (2×75 mL), and the combined organiclayers were washed with brine (100 mL) and dried over sodium sulfate.The drying agent was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by flash column chromatography (silica, 0% to 10%methanol/methylene chloride) followed by trituration with methanol (10mL) to afford 203 in 37% yield (57 mg) as an amorphous white solid: mp170-171° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.74 (d, 1H,J=3.5 Hz), 8.65 (s, 1H), 8.29 (d, 1H, J=10.0 Hz), 7.93 (d, 1H, J=10.0Hz), 7.57 (d, 1H, J=3.5 Hz), 7.43 (t, 1H, J=13.0 Hz), 7.32 (m, 2H), 7.24(d, 1H, J=13.0 Hz), 7.19 (d, 1H, J=13.0 Hz), 4.83 (m, 1H), 4.38 (d, 2H,J=6.5 Hz), 3.60 (s, 3H), 2.90 (s, 2H), 2.74 (s, 2H), 1.28 (s, 6H); MS(ESI+) m/z 526.2 (M+H).

Example 2045-(5-Fluoro-2-(hydroxymethyl)-3-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H) 204

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 197e(170 mg, 0.450 mmol), 182c (300 mg, 0.513 mmol), sodium carbonate (143mg, 1.35 mmol), water (2 mL) and 1,4-dioxane (8 mL). After bubblingnitrogen through the resulting suspension for 30 min,tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) was added,and the reaction mixture was heated at reflux for 2 h. After that time,the mixture was cooled to room temperature and diluted with methylenechloride (100 mL) and water (30 mL). The organic layer was separated,and the aqueous layer was extracted with methylene chloride (3×30 mL).The combined organic layers were dried over sodium sulfate andconcentrated under reduced pressure to afford brown residue.

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with the above cruderesidue, THF (10 mL) and a 1 M solution of tetrabutylammonium fluoridein THF (4.50 mmol, 4.5 mL). The resulting mixture was stirred at roomtemperature for 1 h. After this time, the mixture was diluted withmethylene chloride (100 mL) and washed with water (30 mL). The organiclayer was separated, and the aqueous layer was extracted with methylenechloride (3×30 mL). The combined organic layers were dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica, 0% to 10% methanol/methylenechloride) to afford a 53% yield (154 mg) of 204 as an off-white solid:mp 143-145° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (d, 1H, J=2.5 Hz), 8.35(s, 1H), 7.86 (d, 1H, J=3.0 Hz), 7.34 (m, 3H), 7.21 (d, 1H, J=8.9 Hz),7.17 (dd, 1H, J=9.3, 3.0 Hz), 4.85 (m, 1H), 4.32 (m, 2H), 4.04 (m, 1H),3.85 (m, 1H), 3.58 (s, 3H), 3.03 (m, 5H), 2.87 (m, 1H), 2.75 (s, 2H),2.53 (m, 2H), 2.43 (m, 4H), 2.20 (s, 3H), 1.23 (s, 6H); MS (ESI+) m/z643.3 (M+H).

Example 2052-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one205 Example 205a5-Bromo-1-methyl-3-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one205a

tert-Butyl2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate158c (3.2 g, 7.4 mmol) was suspended in methylene chloride (20 mL),saturated hydrogen chloride in dioxane (20 mL) was added dropwise. Thereaction mixture was stirred for 20 minutes and concentrated underreduced pressure to give 205a, which was used without furtherpurification in the next step. LC/MS: m/z 336 (M+H)⁺

Example 205b5-Bromo-1-methyl-3-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one205b

A mixture of 205a (2.75 g, 7.5 mmol), formaldehyde (37 percent in water,30 ml, 375 mmol), NaBH(OAc)₃ (4.75 g, 22.5 mmol) and acetic acid (25 ml,150 mmol) in methanol (125 ml) was stirred for 4 hours at roomtemperature. The mixture was then brought to basic condition withsaturated NaOH solution and extracted with ethyl acetate. The organiclayer was dried over Na₂SO₄ and evaporated under reduced pressure. Theresidue was purified by column chromatography eluting with 4:1 ethyleacetate/methanol to give 205b (2.0 g, 77%). LC/MS: m/z 349 (M+H)⁺

Example 205c4-Fluoro-2-(1-methyl-5-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 205c

A 15 mL microwave reaction vial with a magnetic stirrer was charged with205b (0.35 g, 1 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (0.48 g, 1 mmol), potassium phosphate (0.54 g, 2 mmol),sodium acetate (0.17 g, 2 mmol), acetonitrile (10 mL), water (1 mL), and1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane (0.08 g, 0.1 mmol). The mixture was heated at 110° C.for 2 hours under argon atmosphere. After this time, the mixture wascooled to room temperature and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified bycolumn-chromatography eluting with 40:1 DMC/methanol to give 205c (0.22g, 36%). LC/MS: m/z 625 (M+H)⁺

A 25 mL round bottomed flask with a magnetic stirrer was charged withcompound4-fluoro-2-(1-methyl-5-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 205c (0.2 g, 0.32 mmol), LiOH (2 g, 48 mmol), THF (5 mL),isopropanol (5 mL) and water (2 mL). The reaction mixture was stirred atroom temperature for 30 minutes and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified byprep-HPLC to give 205 (100 mg, 53%). LC/MS: m/z 583 (M+H)⁺. ¹H NMR (500MHz, DMSO) δ 8.79 (d, J=2, 1H), 8.45 (s, 1H), 7.44 (d, J=2, 1H), 7.31(m, 2H), 7.20 (m, 1H), 7.08 (d, J=9, 1H), 6.52 (s, 1H), 4.89 (m, 1H),4.34 (m, 2H), 4.17 (m, 3H), 3.89 (m, 1H), 3.59 (s, 3H), 3.38 (m, 2H),2.75 (m, 2H), 2.62 (m, 4H), 2.51 (m, 2H), 2.33 (s, 3H), 1.70 (m, 4H).

Example 2062-(2-(Hydroxymethyl)-3-(1-methyl-5-(1-(2-(methylamino)ethyl)-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one206 Example 206a2-(2-(3-Nitro-1H-pyrazol-1-yl)ethyl)isoindoline-1,3-dione 206a

A solution of 4-nitro-1H-pyrazole (10 g, 88.5 mmol) in anhydrous DMF(250 mL) was treated with 60% dispersion of NaH in mineral oil (4.6 g,115 mmol) while stirring under nitrogen. After effervescence thereaction was stirred for an additional 30 minutes. At this time thereaction was treated with 2-(2-bromoethyl)isoindoline-1,3-dione (18-2)(25 g, 97.3 mmol) and continued to stir under nitrogen for 3 hours.Water (50 mL) was then added slowly and the mixture was filtered to give206a as a white solid (20 g, 80%), which was used directly withoutfurther purification. LCMS: (M+H)+287.

Example 206b 2-(3-Nitro-1H-pyrazol-1-yl)ethanamine 206b

A solution of 206a (2.0 g, 7.0 mmol) in ethanol (30 mL) was addedhydrazine hydrate (1 mL, 21 mmol) and the mixture was stirred at roomtemperature for 3 hours. The mixture was evaporated and the residue waspurified by silica-gel eluting with 10:1 methylene chloride/methanol togive 206b as a white solid (0.8 g, 80%). MS: (M+H)⁺ 157.

Example 206c tert-Butyl 2-(3-Nitro-1H-pyrazol-1-yl)ethylcarbamate 206c

To a solution of 206b (18 g, 115 mmol) in methylene chloride (400 mL)was added (Boc)₂O (50 g, 230 mmol) and triethylamine (35 g, 346 mmol).The mixture was stirred at room temperature for 5 hours. It was thenevaporated and purified by silical-gel column eluting with 1:1 petroleumether/ethyl acetate to give 206c as a white solid (24 g, 80%). MS:(M+H)⁺ 257.

Example 206d tert-ButylMethyl(2-(3-nitro-1H-pyrazol-1-yl)ethyl)carbamate 206d

To a solution of 206c (5 g, 19.5 mmol) in THF (40 mL) was added NaH (938mg, 23.4 mmol). The reaction mixture was stirred at room temperature for30 minutes. Iodomethane (1.7 mL, 25.4 mmol) was added and the mixturewas stirred for additional 15 hours. It was then evaporated and purifiedby silical-gel column eluting with 2:1 petroleum ether/ethyl acetate togive 206d as a white solid (4.5 g, 85%). MS: (M+H)⁺ 271.

Example 206e tert-Butyl2-(3-Amino-1H-pyrazol-1-yl)ethyl(methyl)carbamate 206e

To a solution of 206d (4.5 g, 1.7 mmol) in ethanol (40 mL) was added Fe(4.7 g, 8.5 mmol) and NH₄Cl (900 mg, 17 mmol). The reaction mixture wasstirred at room temperature for 4 hours. It was then evaporated andpurified by silical-gel column eluting with 2:1 petroleum ether/ethylacetate to give 206e as a brown solid (3.2 g, 80%). MS: (M+H)⁺ 241.

Example 206f tert-Butyl2-(3-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-1H-pyrazol-1-yl)ethyl(methyl)carbamate206f

A mixture of (206e (2 g, 8.3 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (2.2 g, 8.3 mmol), XantPhos (482mg, 0.83 mmol), Pd₂(dba)₃ (762 mg, 0.83 mmol) and Cs₂CO₃ (6.8 g, 21mmol) in dioxane (80 mL) was heated at 100° C. for 15 h under nitrogen.It was then filtered, evaporated in vacuo, and purified by silical-gelcolumn eluting with 1:2 petroleum ether/ethyl acetate to give 206f as ayellow solid (2.7 g, 77%). MS: (M+H)⁺ 426.

Example 206g2-(5-(1-(2-(tert-Butoxycarbonyl(methyl)amino)ethyl)-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 206g

A mixture of 206f (800 mg, 1.9 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (114a) (873 mg, 1.9 mmol), CH₃COONa (309 mg, 3.8 mmol),PdCl₂(dppf) (153 mg, 0.19 mmol) and K₃PO₄ (1 g, 3.8 mmol) suspended inCH₃CN (30 mL) and H₂O (2 mL) was heated at 110° C. for 15 h under argonatmosphere. It was then evaporated and the residue was purified byreverse phase Combi-flash eluting with 0.3% NH₄HCO₃ in 1:4 water/CH₃CNto give 206g as a brown solid (800 mg, 63%). MS: (M+H)⁺ 684

Example 206h tert-Butyl2-(3-(5-(2-(Hydroxymethyl)-3-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-1H-pyrazol-1-yl)ethyl(methyl)carbamate206h

To a solution of 206g (750 mg, 1.1 mmol) in propan-2-ol (15 mL),tetrahydrofuran (15 mL), and water (5 mL) was added LiOH (2.6 g, 110mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by reverse phase Combi-flash eluting with0.3% NH₄HCO₃ in 1:3 water/CH₃CN to give 206h as a brown solid (500 mg,71%). MS: (M+H)⁺ 642

A solution of 206h (500 mg, 0.78 mmol) in HCl/ethyl acetate (5 mL) wasstirred at room temperature for 2 h. It was then evaporated and theresidue was purified by prep-HPLC to afford 206 as a brown solid (134mg, 35%). MS: (M+H)⁺542. ¹H NMR (500 MHz, MeOD) δ 1.79 (s, 2H), 1.89 (s,2H), 2.35 (s, 3H), 2.54-2.56 (t, J=6 Hz, 2H), 2.63-2.67 (m, 2H),2.97-2.99 (t, J=6 Hz, 2H), 3.71 (s, 3H), 4.00-4.03 (m, 1H), 4.14-4.23(m, 5H), 4.50-4.60 (m, 2H), 6.06-6.07 (d, 1H), 6.71 (s, 1H), 7.23-7.24(d, 1H), 7.37-7.43 (m, 2H), 7.49-7.52 (m, 2H), 8.01-8.02 (d, 1H).

Example 2072-(3-(5-(5-(3-Hydroxy-3-methylazetidin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one207 Example 207a 3-Methyl-1-(6-nitropyridin-3-yl)azetidin-3-ol 207a

A mixture of 5-bromo-2-nitropyridine (3.28 g, 16.3 mmol), XantPhos (1.13g, 1.96 mmol), Pd₂dba₃ (1.19 g, 1.30 mmol), 3-methylazetidin-3-olhydrochloride (2 g, 16.3 mmol) and Cs₂CO₃ (15.9 g. 48.9 mmol) in1,4-dioxane (70 mL) was heated at reflux for 2 h. After the completionof the reaction, the mixture was filtered off, and washed with MeOH (100mL). The filtrate was evaporated in vacuo and the residue was purifiedon reverse phase Combi-flash to give 207a (2.5 g, 71%). MS: [M+H]⁺ 210.

Example 207b 1-(6-Aminopyridin-3-yl)-3-methylazetidin-3-ol 207b

A 100-mL Parr hydrogenation bottle was purged with nitrogen and chargedwith 207a (2.3 g, 11 mmol), 10% palladium on carbon (50% wet, 1.0 g) andmethanol (100 mL). The bottle was evacuated, charged with hydrogen gasto a pressure of 25 psi and shaken for 2 h on a Pan hydrogenationapparatus. The hydrogen was then evacuated and nitrogen charged to thebottle. The catalyst was removed by filtration through a pad of Celiteand the filtrate was concentrated under reduced pressure to afford 207b(1.85 g, 92%). MS: [M+H]⁺ 180.

Example 207c5-Bromo-3-(5-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one207c

A mixture of 207b (1.84 g, 10.3 mmol), XantPhos (714 mg, 1.24 mmol),Pd₂dba₃ (755 mg, 0.82 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (3.27g, 12.3 mmol) and Cs₂CO₃ (10 g. 30.9 mmol) in 1,4-dioxane (50 mL) washeated at reflux for 2 h. After the completion of the reaction, themixture was filtered off, and washed with MeOH (100 mL). The filtratewas evaporated in vacuo and the residue was purified on reverse phaseCombi-flash to give 207c (2.11 g, 54%). MS: [M+H]⁺ 365.

Example 207d2-(5-(5-(3-Hydroxy-3-methylazetidin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 207d

A mixture of 207c (364 mg, 1.0 mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (510 mg, 1.1 mmol), PdCl₂(dppf) (110 mg, 0.15 mmol), K₃PO₄(100 mg), and NaOAc (50 mg) in MeCN (20 mL) and water (4 mL) was heatedat reflux for 2 h. The solvent was evaporated in vacuo and the residuewas purified on reverse phase Combi-flash to give 207d (267 mg, 43%).MS: [M+H]⁺ 623.

A mixture of 207d (350 mg, 0.56 mmol) and LiOH hydrate (236 mg, 5.6mmol) in ^(i)PrOH (20 mL) and water (4 mL) was stirred at 30° C. for 2h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (20 mL×2). The combined extracts were concentratedunder reduced pressure. And the residue was purified on prep-HPLC togive 207 (130 mg, 40%). MS: [M+H]⁺ 581. ¹H NMR (500 MHz, DMSO) δ 8.48(s, 1H), 8.25 (s, 1H), 7.48-7.44 (m, 2H), 7.34-7.28 (m, 3H), 7.17 (d,J=8.5, 1H), 6.89-6.87 (m, 1H), 6.51 (s, 1H), 5.47 (s, 1H), 4.84-4.83 (m,1H), 4.33 (d, J=4.5, 2H), 4.18-4.06 (m, 3H), 3.90-3.86 (m, 1H), 3.70 (d,J=7.5, 2H), 3.58 (s, 3H), 3.53-3.52 (m, 2H), 2.64-2.54 (m, 2H),2.47-2.45 (m, 2H), 1.82-1.75 (m, 2H), 1.73-1.65 (m, 2H), 1.43 (s, 3H).

Example 2082-(3-(5-(6-Ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one208 Example 208a2-(5-(6-Ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 208a

Following Example 136e,5-bromo-3-(6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1-methylpyridin-2(1H)-oneand4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d was converted to 208a in 42% yield. LCMS: (M+H)⁺ 639

Following Example 136, 208a was converted to 208 in 40% yield. LCMS:(M+H)⁺ 597. ¹H NMR (500 MHz, DMSO) δ 8.80 (d, J=2, 1H), 8.45 (s, 1H),7.45 (d, J=2, 1H), 7.31 (m, 2H), 7.20 (dd, J=10, 1H), 7.07 (d, J=9, 1H),6.53 (s, 1H), 4.36 (s, 2H), 4.14 (m, 3H), 3.90 (m, 1H), 3.60 (s, 3H),2.74 (m, 2H), 2.68 (m, 2H), 2.59 (m, 2H), 2.47 (m, 3H), 1.79 (m, 2H),1.69 (m, 2H), 1.08 (t, J=7.5, 3H).

Example 2095-[2-(Hydroxymethyl)-3-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one209 Example 209a{2-[1-Methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxopyridin-3-yl]-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl}methylAcetate 209a

Following Example 148c, 481 mg of 111a and 420 mg of5-bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridine-2-ylamino)pyridin-2(1H)-one188e were reacted to give 209a as a yellow solid (347 mg, 50%). MS:[M+H]⁺ 695

Following Example 148, 230 mg of 209a was converted to 209 as a whitesolid (108 mg, 50%). MS: [M+H]⁺ 653. ¹H NMR (500 MHz, DMSO) δ 8.56 (d,J=2.5, 1H), 8.37 (s, 1H), 7.86 (d, J=3.0, 1H), 7.45 (d, J=7.5, 1H),7.36-7.30 (m, 4H), 7.23 (d, J=9.0, 1H), 4.82 (s, 1H), 4.55 (t, J=6.5,2H), 4.45 (t, J=6.0, 2H), 4.35 (s, 2H), 4.02 (m, 1H), 3.82 (m, 1H), 3.58(s, 3H), 3.42 (m, 2H), 3.06 (t, J=4.5, 4H), 2.92-2.80 (m, 2H), 2.78 (s,2H), 2.53 (m, 1H), 2.38 (s, 4H), 1.80 (s, 4H).

Example 2102-(5-fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one210 Example 210a5-Bromo-1-methyl-3-[5-(4-tert-butoxycarbonylpiperazin-1-yl)-pyridin-2-ylamine210a

Step 1: tert-Butyl 4-(6-Nitropyridin-3-yl)piperazine-1-carboxylate

To solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L)were added K₂CO₃ (40 g, 296 mmol) and tert-butylpiperazine-1-carboxylate (28 g, 148 mmol). The mixture was stirred at65° C. overnight. After cooling down, it was poured into water (2 L).The solid precipitated was collected and dried under vacuum. It was thenpurified by flash column eluting with PE:EA (20:1) and then DCM to give17 gm of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate as ayellow solid (37% yield). MS: [M+H]⁺ 309

Step 2: tert-Butyl 4-(6-Aminopyridin-3-yl)piperazine-1-carboxylate

A 500-mL bottle was purged with nitrogen and charged with tert-butyl4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (3.1 g, 10 mmol), 10%palladium on carbon (50% wet, 1 g) and ethanol (100 mL). The bottle wasevacuated, charged with hydrogen gas, and stirred for 16 h at roomtemperature. The hydrogen was then evacuated and nitrogen charged intothe bottle. The catalyst was removed by filtration through a pad ofCelite and the filtrate concentrated under reduced pressure to affordtert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (2.7 g, 97%).MS: [M+H]⁺ 279

Step 3

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 1,4-dioxane (50 mL),tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, preparedaccording to U.S. Pat. No. 7,456,168, (1.3 g, 4.7 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (1.24 g, 4.7 mmol) and cesiumcarbonate (3.8 g, 12 mmol). After bubbling nitrogen through theresulting solution for 30 min, Xantphos (272 mg, 0.47 mmol) andtris(dibenzylideneacetone)dipalladium(0) (430 mg, 0.47 mmol) were added,and the reaction mixture was heated at reflux for 3 h. After this timethe reaction was cooled to room temperature, partitioned between ethylacetate (100 mL) and water (100 mL) and filtered. The aqueous layer wasseparated and extracted with ethyl acetate (2×50 mL). The organic layerswere combined and washed with brine (50 mL) and dried over sodiumsulfate. The drying agent was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified on flashcolumn eluting with DCM:MeOH (50:1) to afford 210a (1.3 g, 59%). MS:[M+H]⁺ 464.

Example 210b5-Bromo-1-methyl-3-[5-(piperazin-1-yl)-pyridin-2-ylamino]-1H-pyridin-2-one210b

Compound 210a (3.6 g, 7.8 mmol) was suspended in 4.0 M HCl/dioxane (10mL). The reaction mixture was stirred for 5 h at room temperature andconcentrated at reduced pressure. The desired product was basified withaqueous 1.0 M NaOH and was extracted with methylene chloride. Thecombined organic layers were washed with H₂O and concentrated underreduced pressure to give 2.46 g of 210b with an 87% yield. MS: [M+H]⁺364.

Example 210c5-Bromo-1-methyl-3-[5-(4-(oxetan-3-yl)piperazin-1-yl)-pyridin-2-ylamino]-1H-pyridin-2-one210c

A mixture of 210b (2.75 g, 7.5 mmol), oxetan-3-one (1.6 g, 22.7 mmol),NaBH₃CN (4.75 g, 22.5 mmol) and zinc chloride (3 g, 22.7 mmol) inmethanol (125 mL) was stirred for 5 hours at 50 degree. The mixture wasadded to water and extracted with methylene chloride three times. Theorganic layers were concentrated under reduced pressure. The residue waspurified by column-chromatography eluting with methylene chloride:methanol=25:1 to give 210c (1.92 g, 61%). MS: [M+H]⁺ 420. ¹H NMR (500MHz, DMSO) δ 8.58 (d, J=2.5, 1H), 8.55 (s, 1H), 7.94 (d, J=3, 1H), 7.54(d, J=2.5, 1H), 7.39 (dd, J=3, 1H), 7.25 (d, J=4, 1H), 4.56 (t, J=6.5,2H), 4.46 (t, J=6.5, 2H), 3.50 (s, 3H), 3.43 (m, 1H), 3.01 (m, 4H), 2.40(m, 4H).

Example 210d2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 210d

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with 197d (3.8 g, 8.65 mmol), bis(pinacolato)diboron(11 g, 43.25 mmol), Pd(dppf)Cl₂ (0.4 g, 0.5 mmol), KOAc (2.5 g, 26mmol), and 1,4-dioxane (150 mL). The system was evacuated and thenrefilled with N₂. A reflux condenser was attached to the flask, and thereaction mixture was heated at 100° C. for 15 h. It was then cooled toroom temperature and filtered. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by flash columnchromatography eluting with 5:1 petroleum ether/ethyl acetate to afford210d in 77% yield (3.2 g) as a yellow solid. MS: [M+H]⁺ 483.

Example 210e5-Fluoro-2-(1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 210e

A sealed tube was charged with the mixture of 210d (337 mg, 0.7 mmol),210c (294 mg, 0.7 mmol), Pd(dppf)Cl₂ (33 mg, 0.04 mmol), K₃PO₄.3H₂O (372mg, 1.4 mmol), and NaOAc (115 mg, 1.4 mmol) in 20 mL CH₃CN. The systemwas evacuated and refilled with N₂. The reaction mixture was heated at110° C. for 2 h. It was then cooled to room temperature and filtered.The filtrate was concentrated under reduced pressure, and the resultingresidue was purified by flash column chromatography eluting with 30:1DCM/MeOH to afford 210e in 54% yield (263 mg) as a yellow solid. MS:[M+H]⁺ 696.

At room temperature, to the solution of 210e (250 mg, 0.36 mol) inTHF/iso-propanol/water (6 mL/6 mL/2 mL) was added LiOH (87 mg, 3.6 mmol)while stirring. This mixture was stirred for 0.5 h. Then, 20 mL of waterwas added and extracted with ethyl acetate (30 mL×3). The combinedorganic layer was dried with Na₂SO₄ and concentrated to get a yellowsolid which was further purified by prep-HPLC to afford 210 as a whitesolid (134 mg, 57% yield). LCMS: [M+H]⁺ 654. ¹H NMR (500 MHz, MEOD) δ8.53 (d, J=2.5, 1H), 7.93 (d, J=3, 1H), 7.42 (dd, J=3, 1H), 7.34 (d,J=2.5, 1H), 7.23 (s, 1H), 7.21 (s, 1H), 7.03 (d, J=4.5, 1H), 6.72 (s,1H), 4.73 (t, J=2, 2H), 4.64 (t, J=1.5, 2H), 4.51 (m, 2H), 4.21 (s, 3H),4.03 (m, 1H), 3.71 (s, 3H), 3.57 (m, 1H), 3.17 (t, J=4.5, 4H), 2.65 (m,2H), 2.55 (m, 6H), 1.90 (m, 2H), 1.79 (m, 2H)

Example 2115-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one211 Example 211a{4-Fluoro-2-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}phenyl}methylAcetate 211a

Following Example 148h, 400 mg of(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 212b and 336 mg of5-bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridine-2(1H)-one210c were reacted to give 211a as a yellow solid (319 mg, 56%). LCMS:(M+H)⁺ 713

Following Example 148, 270 mg of 211a was converted to 211 as a whitesolid (120 mg, 48%). LCMS: [M+H]⁺ 671. ¹H NMR (500 MHz, DMSO) δ 8.56 (s,1H), 8.39 (s, 1H), 7.87 (s, 1H), 7.38-7.16 (m, 5H), 4.8 (s, 1H), 4.56(t, J=6.5 2H), 4.46 (t, J=6.5, 2H), 4.33 (s, 1H), 4.05 (m, 1H), 3.87 (m,1H), 3.58 (s, 3H), 3.43 (t, J=6, 2H), 3.06 (m, 4H), 2.88-2.78 (m, 4H),2.38 (t, J=5, 1H), 1.79 (m, 4H).

Example 2125-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one212 Example 212a2-Bromo-4-fluoro-6-(1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzylAcetate 212a

A solution of 104e (3 g, 14.5 mmol), 2,6-dibromo-4-fluorobenzyl acetate197c (14 g, 43.5 mmol), Xantphos (839 mg, 1.45 mmol), Pd₂(dba)₃ (1.33 g,1.45 mmol) and Cs₂CO₃ (9.4 g, 29 mmol) in dioxane (200 mL) was heated at100° C. for 15 h under nitrogen. After filtration, the filtrate wasevaporated in vacuo and purified by flash column eluting with ethylacetate/petroleum ether (1:1) to give 212a (5 g, yield 77%) as a yellowsolid. LCMS: (M+H)⁺ 452. ¹H NMR (500 MHz, DMSO) δ 7.71 (dd, J=2.5, 1H),7.51 (dd, J=3, 1H), 5.04 (m, 1H), 4.10 (m, 1H), 3.68 (m, 1H), 2.86 (m,2H), 2.77 (m, 2H), 2.55 (m, 3H), 1.98 (s, 3H), 1.78 (m, 4H).

Example 212b2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-fluoro-6-(1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzylAcetate 212b

A solution of 212a (3 g, 6.65 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxa-borolane) (10 g, 40mmol) in dioxane (160 mL) was added PdCl₂(dppf) (543 mg, 0.66 mmol) andCH₃COOK (3.9 g, 40 mmol). The mixture was stirred at 100° for 15 h underargon atmosphere. The mixture was filtered and evaporated in vacuo andpurified by flash column eluting with ethyl acetate/petroleum ether(1:2) to give 212b (2.5 g, yield 76%) as a yellow solid. LCMS: (M+H)⁺500

Example 212c[4-Fluoro-2-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 212c

A 25 mL sealed tube was charged with 212b (990 mg, 2 mmol),5-bromo-1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridine-2(1H)-one198e (500 mg, 1.3 mmol), CH₃COONa (220 mg, 2.6 mmol), K₃PO₄ (700 mg, 2.6mmol), and PdCl₂(dppf) (110 mg, 0.13 mmol) suspended in CH₃CN (25 mL)and water (1 mL). The mixture was heated at 110° C. for 2 hours. It wasevaporated and the residue was purified by silical-gel column elutingwith 20:1 methylene chloride/methanol to give 212c as a brown solid (500mg, 56%). LCMS: [M+H]⁺ 670

To a solution of 212c (500 mg, 0.75 mmol) in propan-2-ol (8 mL),tetrahydrofuran (8 mL), and water (1.5 mL) was added LiOH (964 mg, 40mmol). The mixture was stirred at 30° C. for 2 h. Then, 20 mL H₂O wasadded and the mixture was extracted with ethyl acetate (3×30 mL). Thecombined organic layer was dried with Na₂SO₄ and concentrated to give ayellow solid, which was further purified by prep-HPLC to give 212 as awhite solid (200 mg, 48%). LCMS: [M+H]⁺ 629. ¹H NMR (500 MHz, DMSO-d₆) δ8.56 (d, J=2, 1H), 8.37 (s, 1H), 7.85 (d, J=2.5, 1H), 7.34 (m, 3H), 7.19(m, 2H), 4.86 (s, 1H), 4.32 (s, 2H), 4.05 (m, 1H), 3.87 (m, 1H), 3.57(s, 3H), 3.02 (m, 4H), 2.96 (m, 1H), 2.87 (m, 1H), 2.77 (m, 2H), 2.54(m, 1H), 2.43 (m, 4H), 2.19 (s, 3H), 1.79 (m, 4H).

Example 2132-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one213 Example 213a4-Fluoro-2-(1-methyl-5-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 213a

Following Example 148b, 482 mg of4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d and 350 mg5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridin-2(1H)-one172a, were reacted to give 213a as a yellow solid (324 mg, 52%). MS:[M+H]⁺ 625.

Following the procedures as described for 148 and starting with 220 mgof 213a, compound 213 was obtained as a white solid (82 mg, 40%). MS:[M+H]⁺ 583. ¹H NMR (500 MHz, CDCl3) δ 8.64 (d, J=2.0, 1H), 8.13 (d,J=2.5, 1H), 7.89 (s, 1H), 7.58 (m, 1H), 7.50 (d, J=2.5, 1H), 7.16 (dd,J=9.0, 1H), 6.96 (dd, J=8.5, 1H), 6.86 (s, 1H), 6.83 (d, J=8.5, 1H),4.55 (d, J=11.5, 1H), 4.40 (s, 1H), 4.30 (s, 1H), 4.16 (m, 2H), 3.91 (m,1H), 3.72 (m, 5H), 3.60 (m, 1H), 3.14 (t, J=7.0, 2H), 2.59 (m, 4H), 2.38(s, 3H), 1.90-1.79 (m, 5H).

Example 2142-(5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one214 Example 214a5-Bromo-1-methyl-3-(4-(piperidin-4-yl)phenylamino)pyrazin-2(1H)-one 214a

Compound 214a was synthesized using the same procedure as for 121c,except using tert-butyl4-(4-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-piperidine-1-carboxylate(121a) (0.53 g, 1.08 mmol), trifluoroacetic acid (0.9 mL, 10.8 mmol) andmethylene chloride (20 mL). Work-up and concentration afforded aquantitative yield of 214a (390 mg) as yellow oil, which was usedwithout purification in the next step.

Example 214b5-Bromo-1-methyl-3-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)-pyrazin-2(1H)-one214b

A 100-mL sealed tube with a magnetic stirrer was purged with nitrogenand charged with 214a (390 mg, 1.08 mmol), oxetan-3-one (800 mg, 11mmol) and methanol (10 mL). A suspension of sodium cyanoborohydride (208mg, 3.3 mmol) and zinc chloride (225 mg, 1.65 mmol) in methanol (10 mL)was added, and the reaction was heated at 48° C. for 12 hours. Afterthis time, the reaction mixture was concentrated, and the residue waspartitioned between ethyl acetate (50 mL) and 10% aqueous potassiumcarbonate (10 mL). The aqueous layer was extracted with ethyl acetate(3×30 mL). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure. The resulting residue waspurified by column chromatography (silica, 60:35:5 methylenechloride/diethyl ethyl/methanol) to afford a 60% yield (270 mg) of5-bromo-1-methyl-3-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)pyrazin-2(1H)-one(214b) as a yellow solid: MS (ESI+) m/z 421.2 (M+H).

Example 214c4-Fluoro-2-(4-methyl-6-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 214c

Following Example 121b,4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (217 mg, 0.45 mmol), 214b (158 mg, 0.375 mmol), 1M sodiumcarbonate solution (1.5 mL, 1.5 mmol),tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol) and1,2-dimethoxyethane (3.5 mL) were heated at 130° C. for 15 minutes inthe microwave reactor. Work-up and flash column chromatography (silica,60:35:5 methylene chloride/diethyl ether/methanol) give a 62% yield (160mg) of 214c as brown oil: MS (ESI+) m/z 696.1 (M+H).

Compound 214 was synthesized using the same procedure as for 121, exceptusing a mixture of THF (1 mL), water (0.5 mL) and isopropanol (1 mL),214c (160 mg, 0.23 mmol) and lithium hydroxide monohydrate (80 mg, 2mmol). Work-up and flash column chromatography (NH-silica, ethylacetate/Hexanes) give a 34% yield (52 mg) of 214 as a yellow solid: MS(ESI+) m/z 653.6 (M+H).

Example 21510-[5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-{[4-(1-methylazetidin-3-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one215 Example 215a10-[5-Fluoro-2-(acetoxymethyl)-3-(4-methyl-6-{[4-(1-methylazetidin-3-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one215a

A 44-mL sealed tube equipped with a magnetic stirrer was charged with298c (160 mg, 0.48 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (180 mg, 0.71mmol), potassium acetate (188 mg, 1.9 mmol) and 1,4-dioxane (5 mL).After the mixture was degassed for 30 minutes, Pd(dppf)Cl₂.CH₂Cl₂ (39mg, 0.048 mmol) was added. The resulting reaction mixture was stirred at105° C. for 4 h. Then, it was cooled to room temperature and filteredthrough a pad of Celite. The filtrate was concentrated, and the crudemixture was redissolved in 1,2-dimethoxyethane (2 mL) and transferredinto a 10-mL microwave reaction vessel. To this solution was added10-[2-(acetoxy-methyl)-3-bromo-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one189a (172 mg, 0.38 mmol), Pd(PPh₃)₄ (30 mg, 0.024 mmol), and 2 N Na₂CO₃(2 mL). Then, the reaction mixture was degassed for 5 minutes and placedinto the microwave cavity. After the reaction mixture was stirred at125° C. for 10 min., it was purified by flash chromatography(dichloromethane:methanol, 3:1) to give 20% (49 mg) of 215a.

A 25-mL, single-necked, round-bottomed flask equipped with a magneticstirring bar was charged with 215a (49 mg, 0.077 mmol), LiOH.H₂O (16 mg,0.38 mmol), THF (2 mL), isopropanol (2 mL), and water (2 mL). After thereaction mixture was stirred at room temperature for 3 h, it waspartitioned between dichloromethane (5 mL) and water (5 mL), and theorganic phase was extracted with dichloromethane (3×5 mL). The combinedorganic phases were washed with water (2×5 mL) and brine (5 mL), dried(Na₂SO₄), and concentrated. The crude product was re-dissolved indichloromethane (3 mL). To this solution was added hexane (10 mL) andthe resulting precipitate was filtered to give 74% yield (34 mg) of 215.MS(ESI⁺) m/z 597.5 (M+H).

Example 216 Di-sodium2-(1-Methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydro-pyridin-3-yl)-6-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)benzylPhosphate 216 Example 216a Bis(2-cyanoethyl)2-(1-Methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)-6-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno-[2,3-c]pyridine-1(2H)-yl)benzylPhosphate 216a

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 105 (850 mg, 1.61 mmol),1H-tetrazole (451 mg, 6.44 mmol) and methylene chloride (20 mL). Asolution of bis(2-cyanoethyl)-N,N-diisopropyl phosphoramidite (1.31 g,4.83 mmol) in methylene chloride (5 mL) was added at room temperature,and the reaction mixture was stirred for 3 h under nitrogen atmosphere.After this time, the reaction mixture was cooled to 0° C. and a 5.5 Msolution of tert-butyl hydroperoxide in decane (2.00 mL, 11.0 mmol) wasadded dropwise, and the reaction mixture was stirred at 0° C. for 3 hunder nitrogen atmosphere. After this time, the mixture was concentratedunder reduced pressure to a volume of 5 mL, and the resulting suspensionwas loaded on a silica gel column and eluted with 90:10 methylenechloride/methanol to afford 216a in 39% yield (450 mg) as a whitesemi-solid: ¹H NMR (500 MHz, CDCl₃) δ 8.77 (d, J=0.5 Hz, 1H), 8.73 (d,J=2.0 Hz, 1H), 8.36 (d, J=5.5 Hz, 1H), 8.17 (s, 1H), 7.55 (t, J=7.5 Hz,1H), 7.38-7.35 (m, 2H), 7.09 (d, J=2.0 Hz, 1H), 6.76 (dd, J=6.0, 1.5 Hz,1H), 5.21-5.14 (m, 2H), 4.15-4.04 (m, 5H), 3.86-3.83 (m, 1H), 3.72 (s,3H), 3.21-3.18 (m, 1H), 2.90-2.82 (m, 1H), 2.79 (d, J=3.5 Hz, 2H),2.63-2.48 (m, 6H), 1.28 (s, 3H), 1.27 (s, 3H); MS (ESI+) m/z 714.2(M+H).

Example 216b Di-ammonium2-(1-Methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydro-pyridin-3-yl)-6-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)benzylPhosphate 216b

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 216a (450 mg, 0.631 mmol)and acetonitrile (8 mL), and the mixture was cooled to 0° C.Triethylamine (4 mL) was added followed bis trimethyl-silyltrifluoroacetamide (4 mL), and the mixture was stirred at roomtemperature for 40 h. After this time, the mixture was concentratedunder reduced pressure and the resulting residue was purified by flashcolumn chromatography (silica, 40:20:40 chloroform/methanol/ammonia) toafford 216b in 52% yield (210 mg) as an amorphous yellow solid: mp260-262° C. d; ¹H NMR (500 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.66 (s, 1H),8.62 (d, J=2.0 Hz, 1H), 8.27 (d, J=4.0 Hz, 1H), 7.54 (s, 1H), 7.43 (t,J=7.5 Hz, 1H), 7.32-7.27 (m, 3H), 7.15 (br s, 2H), 4.69 (d, J=9.0 Hz,1H), 4.46 (d, J=7.0 Hz, 1H), 3.87-3.83 (m, 3H), 3.57 (s, 3H), 3.36-3.17(br s, 8H), 2.77-2.63 (m, 3H), 1.23 (s, 3H), 1.21 (s, 3H); MS (ESI+) m/z608.2 (M+H for C₂₉H₃₀N₅O₆PS).

A 200-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with 216b (210 mg, 0.327 mmol), methanol (10 mL) andwater (5 mL). A 0.1 M solution of sodium hydroxide in water (6.50 mL,0.65 mmol) was added at room temperature, and the mixture was stirredfor 30 min. After this time, the mixture was concentrated under reducedpressure and dried under vacuum at 45° C. for 14 h to afford 216 in 92%yield (197 mg) as an amorphous yellow solid: mp 256-258° C. dec; ¹H NMR(500 MHz, DMSO-d₆/D₂O (15:1)) d 8.65 (s, 1H), 8.63 (d, J=1.5 Hz, 1H),8.28 (d, J=6.0 Hz, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H),7.38 (d, J=7.5 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.16 (d, J=6.0 Hz, 1H),4.72 (d, J=9.5 Hz, 1H), 4.45 (d, J=8.0 Hz, 1H), 4.23-4.21 (m, 1H),3.83-3.78 (m, 1H), 3.71 (s, 3H), 3.48-3.41 (m, 1H), 2.78-2.73 (m, 3H),2.59-2.49 (m, 2H), 1.23 (s, 3H), 1.22 (s, 3H); MS (ESI+) m/z 608.2 (M+Hfor C₂₉H₃₀N₅O₆PS).

Example 2175-(5-Fluoro-2-(hydroxymethyl)-3-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-3-(5-(4-(2-fluoroethyl)piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one217 Example 217a 1-(6-Nitropyridin-3-yl)piperazine 217a

A 250-mL three-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 2-nitro-5-bromopyridine(5.00 g, 24.6 mmol), piperazine (5.66 g, 65.7 mmol) and acetonitrile (70mL). The reaction mixture was heated at reflux for 20 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was diluted with ethylacetate (200 mL) and washed with saturated aqueous sodium bicarbonate(100 mL). The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was titratedwith hexane/ethyl acetate (1:1, 30 mL) to afford 217a in 41% yield (2.10g) as a yellow solid: mp 113-115° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.23(d, 1H, J=3.5 Hz), 8.13 (d, 1H, J=9.0 Hz), 7.44 (dd, 1H, J=9.0, 3.5 Hz),3.41 (t, 4H, J=5.0 Hz), 2.82 (t, 4H, J=5.0 Hz), 1.90 (s, 1H); MS (ESI+)m/z 209.1 (M+H).

Example 217b 1-(2-Fluoroethyl)-4-(6-nitropyridin-3-yl)piperazine 217b

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser, and nitrogen inlet was charged with 217a (598mg, 2.87 mmol), 1-bromo-2-fluoroethane (1.09 g, 8.61 mmol), potassiumcarbonate (1.19 g, 8.61 mmol), THF (10 mL) and DMF (10 mL). The reactionmixture was heated at 85° C. for 14 h under nitrogen atmosphere. Afterthis time, the mixture was diluted with 90:10 methylenechloride/methanol (100 mL) and water (75 mL), and the layers wereseparated. The aqueous layer was extracted with 90:10 methylenechloride/methanol (50 mL), and the combined organic layers were washedwith brine (100 mL) and dried over sodium sulfate. The drying agent wasremoved by filtration. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by flash columnchromatography (silica, 95:5 methylene chloride/methanol) to afford 217bin 63% yield (460 mg) as a yellow semi-solid: ¹H NMR (500 MHz, CDCl₃) δ8.16 (d, J=9.0 Hz, 1H), 8.14 (d, J=3.0 Hz, 1H), 7.21 (dd, J=9.0, 2.0 Hz,1H), 4.67 (t, J=5.0 Hz, 1H), 4.57 (t, J=5.0 Hz, 1H), 3.49 (t, J=5.0 Hz,4H), 2.81 (t, J=5.0 Hz, 1H), 2.75 (t, J=5.0 Hz, 1H), 2.73 (t, J=5.5 Hz,4H); MS (ESI+) m/z 255.1 (M+H).

Example 217c 5-(4-(2-Fluoroethyl)piperazin-1-yl)pyridin-2-amine 217c

A 250-mL Parr reactor bottle was purged with nitrogen and charged with10% palladium on carbon (50% wet, 75 mg dry weight) and a solution of217b (455 mg, 1.79 mmol) in ethanol (20 mL). The bottle was attached toa Parr hydrogenator, evacuated, charged with hydrogen gas to a pressureof 50 psi and shaken for 3 h. After this time, the hydrogen wasevacuated, and nitrogen was charged into the bottle. Celite 521 (3.50 g)was added, and the mixture was filtered through a pad of Celite 521. Thefilter cake was washed with ethanol (2×50 mL), and the combinedfiltrates were concentrated to dryness under reduced pressure to afforda quantitative yield of 217c (425 mg) as a yellow semi-solid: ¹H NMR(500 MHz, CDCl₃) δ 7.75 (d, J=3.0 Hz, 1H), 7.20 (dd, J=9.0, 3.0 Hz, 1H),6.51 (d, J=8.5 Hz, 1H), 4.66 (t, J=5.0 Hz, 1H), 4.56 (t, J=5.0 Hz, 1H),4.35-4.15 (br s, 2H), 3.08 (t, J=5.0 Hz, 4H), 2.79 (t, J=5.0 Hz, 1H),2.74 (t, J=4.5 Hz, 1H), 2.71 (t, J=5.0 Hz, 4H); MS (ESI+) m/z 225.1(M+H).

Example 217d5-Bromo-3-(5-(4-(2-fluoroethyl)piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one217d

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 217c (402 mg, 1.79 mmol),3,5-dibromo-1-methyl-pyridin-2(1H)-one (478 mg, 1.79 mmol), cesiumcarbonate (1.75 g, 5.37 mmol) and 1,4-dioxane (15 mL). After bubblingnitrogen through the resulting suspension for 30 min, Xantphos (93 mg,0.161 mmol) and tris(dibenzylideneacetone)dipalladium(0) (82 mg, 0.090mmol) were added. A reflux condenser was attached to the flask, and thereaction mixture was heated at 100° C. for 3 h. After this time, themixture was cooled to room temperature and diluted with 90:10 methylenechloride/methanol (100 mL) and water (75 mL), and the layers wereseparated. The aqueous layer was extracted with 90:10 methylenechloride/methanol (2×50 mL), and the combined organic layers were washedwith brine and dried over sodium sulfate. The drying agent was removedby filtration. The filtrate was concentrated under reduced pressure, andthe resulting residue was purified by flash column chromatography(silica, 95:5 methylene chloride/methanol) to afford 217d in 62% yield(459 mg) as an amorphous yellow solid: mp 141-143° C.; ¹H NMR (500 MHz,CDCl₃) δ 8.57 (d, J=2.0 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 7.74 (s, 1H),7.24 (d, J=3.0 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 6.76 (d, J=9.0 Hz, 1H),4.67 (t, J=5.0 Hz, 1H), 4.57 (t, J=5.0 Hz, 1H), 3.59 (s, 3H), 3.16 (t,J=5.0 Hz, 4H), 2.80 (t, J=5.0 Hz, 1H), 2.75 (t, J=5.0 Hz, 1H), 2.73 (t,J=5.5 Hz, 4H); MS (ESI+) m/z 410.1 (M+H)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 217d (177 mg, 0.431 mmol),182c (315 mg, 0.539 mmol), sodium carbonate (100 mg, 0.862 mmol), water(2 mL) and 1,4-dioxane (10 mL). After bubbling nitrogen through theresulting suspension for 30 min,tetrakis(tripheny-1phosphine)palladium(0) (100 mg, 0.086 mmol) wasadded. A reflux condenser was attached to the flask, and the reactionmixture was heated at 90° C. for 1 h. After this time, the mixture wasdiluted with 90:10 methylene chloride/methanol (100 mL) and water (75mL), and the layers were separated. The aqueous layer was extracted with90:10 methylene chloride/methanol (2×50 mL), and the combined organiclayers were washed with brine (100 mL) and dried over sodium sulfate.The drying agent was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the resulting residue wasdissolved in a mixture of THF. A 1.0 M solution of tetra-butyl-ammoniumfluoride in THF (1.10 mL, 1.10 mmol) was added, and the mixture wasstirred at room temperature for 3 h. After this time, the mixture wasdiluted with 90:10 methylene chloride/methanol (75 mL) and water (50mL), and the layers were separated. The aqueous layer was extracted with90:10 methylene chloride/methanol (2×50 mL), and the combined organiclayers were washed with brine (100 mL) and dried over sodium sulfate.The drying agent was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by flash column chromatography (silica, 95:5 methylenechloride/methanol) to afford 217 in 25% yield (73 mg) as an amorphousyellow solid: mp 158-160° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, J=2.0Hz, 1H), 8.35 (s, 1H), 7.86 (d, J=3.0 Hz, 1H), 7.37-7.31 (m, 3H), 7.22(d, J=9.0 Hz, 1H), 7.17 (dd, J=9.5, 3.0 Hz, 1H), 4.85 (t, J=4.0 Hz, 1H),4.61 (t, J=5.0 Hz, 1H), 4.51 (t, J=5.0 Hz, 1H), 4.35-4.30 (m, 2H),4.08-4.02 (m, 1H), 3.87-3.82 (m, 1H), 3.58 (s, 3H), 3.05-2.99 (m, 5H),2.91-2.87 (m, 1H), 2.75 (s, 2H), 2.68 (t, J=5.0 Hz, 1H), 2.62 (t, J=4.5Hz, 1H), 2.57-2.53 (m, 4H), 2.52 (d, J=4.5 Hz, 2H), 1.23 (s, 6H); MS(ESI+) m/z 675.3 (M+H).

Example 2185-(3-{5-[(6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-5-fluoro-2-(hydroxymethyl)phenyl)-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one218 Example 218a(2-{5-[(6-Ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl)methylAcetate 218a

A 25 mL sealed tube was charged with(2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methylacetate (212b) (893 mg, 1.8 mmol),5-bromo-3-(6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1-methylpyridin-2(1H)-one(500 mg, 1.4 mmol), CH₃COONa (226 mg, 2.75 mmol), K₃PO₄ (733 mg, 2.75mmol), PdCl₂(dppf) (112 mg, 0.14 mmol) suspended in CH₃CN (25 mL) andH₂O (1 mL). The mixture was stirred at 110° C. for 2 hours. Afterreaction the solvent was evaporated and the residue was purified bysilical-gel column eluting with 20:1 methylene chloride/methanol to give218a as a brown solid (400 mg, 44%). MS: (M+H)⁺ 656.

To a solution of 218a (350 mg, 0.53 mmol) in propan-2-ol (10 mL),tetrahydrofuran (10 mL), and water (2 mL) was added LiOH (1.28 g, 53mmol). The mixture was stirred at 30° C. for 2 h. After reaction themixture was evaporated and the residue was purified by prep-HPLC toafford 218 as a yellow solid (124 mg, 38%). MS: (M+H)⁺ 614. ¹H NMR (500MHz, DMSO) δ 1.06-1.09 (t, J=7.5 Hz, 3H), 1.80 (s, 4H), 2.55-2.58 (m,2H), 2.67-2.68 (d, 2H), 2.74-2.79 (d, 4H), 2.85-2.98 (m, 2H), 3.43 (s,2H), 3.60 (s, 3H), 3.87-3.89 (m, 1H), 4.05-4.07 (m, 1H), 4.37-4.38 (d,2H), 4.87-4.89 (t, J=4.5 Hz, 1H), 7.07-7.09 (d, 1H), 7.19-7.21 (m, 1H),7.29-7.34 (m, 2H), 7.45-7.46 (d, 1H), 8.46 (s, 1H), 8.79-8.80 (d, 1H).

Example 2195-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one219 Example 219a5-Bromo-1-methyl-3-(6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one219a

A mixture of5-bromo-1-methyl-3-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridine-2(1H)-onehydrochloride 205a (800 mg, 2.16 mmol), oxetan-3-one (778 mg, 10.8mmol), NaBH₃CN (681 mg, 10.8 mmol), and zinc chloride (1.47 g, 10.8mmol) in methanol (30 mL) was stirred for 4 hours at 50° C. The mixturewas added to H₂O (30 mL) and extracted with DCM (50 mL×3). The organiclayers were concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 10:1 ethylacetate/methanol to give 219a as a yellow solid (750 mg, 89%). MS:[M+H]⁺ 391.

Example 219b[4-Fluoro-2-(1-methyl-5-{[6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 219b

A 25 mL sealed tube was charged with(2-{6-oxo-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 212b (512 mg, 1.0 mmol), 219a (400 mg, 1.0 mmol), CH₃COONa (168mg, 2.0 mmol), K₃PO₄ (546 mg, 2.0 mmol), and PdCl₂(dppf) (84 mg, 0.1mmol) suspended in CH₃CN (25 mL) and H₂O (1 mL). The mixture was stirredin at 110° C. for 2 hours. After reaction the mixture was evaporated andthe residue was purified by column chromatography eluting with 10:1methylene chloride/methanol to give 219b as a brown solid (450 mg, 64%).MS: (M+H)⁺ 684.

A solution of 219b (400 mg, 0.58 mmol) in propan-2-ol (12 mL),tetrahydrofuran (12 mL), and water (2 mL) was added LiOH (1.4 g, 58mmol). The mixture was stirred at 30° C. for 2 h. After reaction themixture was evaporated and the residue was purified by prep-HPLC toafford 219 as a yellow solid (213 mg, 57%). MS: (M+H)⁺ 642. ¹H NMR (500MHz, DMSO) δ 1.80 (s, 4H), 2.55-2.58 (m, 3H), 2.77-2.79 (d, 4H),2.85-2.89 (m, 1H), 2.96-2.98 (m, 1H), 3.36 (s, 2H), 3.60-3.61 (d, 4H),3.87-3.89 (m, 1H), 4.05-4.07 (m, 1H), 4.37-4.38 (d, 2H), 4.50-4.52 (t,J=5 Hz, 2H), 4.59-4.62 (t, J=6.5 Hz, 2H), 4.87-4.90 (t, J=4 Hz, 2H),7.08-7.10 (d, 1H), 7.19-7.21 (m, 1H), 7.29-7.34 (m, 2H), 7.45-7.46 (d,1H), 8.46 (s, 1H), 8.79-8.80 (d, 1H).

Example 2205-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]pyridin-2-yl}amino)-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-6-one220 Example 220a5-Bromo-3-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one220a

A mixture of5-bromo-1-methyl-3-(5-(piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one188d (1.2 g, 3.3 mmol), and acetone (1.0 g, 16.5 mmol) inmethanol/acetic acid (30 mL/3 mL) was stirred for 5 minutes at roomtemperature, followed by the addition of NaBH(OAc)₃ (3.5 g, 16.5 mmol).The mixture was stirred at 50° C. for 2 h. It was cooled to roomtemperature and H₂O (50 mL) was added. The mixture was extracted withDCM (50 mL) three times. The organic layers were concentrated underreduced pressure and the residue was purified by column chromatographyeluting with 25:1 DCM/methanol to give 220a (2.97 g, 81%). MS: [M+H]⁺406. ¹H NMR (500 MHz, DMSO) δ 8.58 (d, J=3.0, 1H), 8.53 (s, 1H), 7.92(d, J=3.0, 1H), 7.44 (d, J=2.5, 1H), 7.37 (d, J=2.5, 1H), 7.25 (d, J=8,1H), 3.51 (s, 3H), 3.06 (t, J=4.5, 4H), 2.69 (s, 1H), 2.57-2.50 (m, 4H),1.00 (d, J=7, 6H).

Example 220b{4-Fluoro-2-[1-methyl-6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]pyridin-2-yl}amino)-1,6-dihydropyridin-3-yl]-6-{6-oxo-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl}methylAcetate 220b

Following the procedures as described for 148b and starting with 400 mgof(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 212b and 340 mg5-bromo-3-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one220a, compound 220b was obtained as a yellow solid (446 mg, 82%). MS:[M+H]⁺ 699

Following the procedures as described for 148 and starting with 200 mgof 220b, compound 220 was obtained as a white solid (70 mg, 37%). MS:[M+H]⁺ 657. ¹H NMR (500 MHz, DMSO) δ 8.56 (d, J=2.5, 1H), 8.37 (s, 1H),7.85 (d, J=2.5, 1H), 7.34 (m, 3H), 7.23 (m, 2H), 4.68 (s, 1H), 4.32 (s,2H), 4.06 (s, 1H), 3.85 (s, 1H), 3.58 (s, 3H), 3.02 (s, 4H), 2.78 (m,4H), 2.55 (m, 7H), 1.80 (d, J=3.5, 4H), 1.00 (d, J=7, 6H).

Example 2215-[5-Fluoro-2-(hydroxymethyl)-3-{4-methyl-6-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one221 Example 221a5-Bromo-1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one221a

To a solution of tert-butyl6-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate120a (3.6 g, 8.3 mmol) in dioxane (10 mL) was added saturated hydrogenchloride solution in dioxane (20 mL) dropwise. The reaction mixture wasstirred for 20 minutes and concentrated under reduced pressure to give221a, which was used without further purification in the next step.LC/MS: m/z 336 (M+H)⁺

Example 221b5-Bromo-1-methyl-3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one221b

A mixture of 221a (2.75 g, 7.5 mmol), formaldehyde (37% in H₂O, 30 mL,375 mmol), NaBH(OAc)₃ (4.75 g, 22.5 mmol), and AcOH (25 ml, 150 mmol) inmethanol (125 ml) was stirred for 4 hours at room temperature. Themixture was then brought to basic condition with saturated NaOH solutionand extracted with ethyl acetate. The organic layer was dried overNa₂SO₄ and evaporated under reduced pressure. The residue was purifiedby column chromatography eluting with 4:1 ethyl acetate/methanol to give221b. (0.9 g, 34.4%) LC/MS: m/z 350 (M+H)⁺

Example 221c(4-Fluoro-2-{4-methyl-6-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}phenyl)methyl Acetate 221c

A 15 mL microwave vial with a magnetic stirrer was charged with5-bromo-1-methyl-3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one(0.42 g, 1.2 mmol), 212b (0.6 g, 1.2 mmol), potassium phosphate (0.64 g,2.4 mmol), sodium acetate (0.2 g, 2.4 mmol), acetonitrile (10 mL), water(1 mL), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.1 g, 0.12 mmol). The reaction mixture washeated at 110° C. for 2 hours under argon atmosphere. After this time,the mixture was cooled to room temperature and filtered. The filtratewas concentrated under reduced pressure and the residue was purified bycolumn chromatography eluting with 40:1 DMC/methanol to give 221c (0.667g, 86.6%). LC/MS: m/z 642 (M+H)⁺

A 25 mL round bottomed flask with a magnetic stirrer was charged with221c (0.647 g, 1.0 mmol), LiOH (2.1 g, 50 mmol), THF (10 mL),isopropanol (10 mL) and water (5 mL). The reaction mixture was stirredat room temperature for 30 minutes and filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified byprep-HPLC to give 221. LC/MS: m/z 600 (M+H)⁺. ¹H NMR (500 MHz, DMSO) δ9.13 (s, 1H), 7.80 (s, 1H), 7.62 (d, J=8.5, 1H), 7.51 (s, 1H), 7.39 (d,J=10, 1H), 7.30 (d, J=6.5, 1H), 6.97 (d, J=8.5, 1H), 4.86 (m, 1H), 44.51(m, 3H), 4.41 (m, 1H), 4.05 (m, 1H), 3.87 (m, 1H), 3.55 (m, 6H), 2.77(m, 3H), 2.55 (m, 3H), 2.31 (m, 3H), 1.80 (m, 4H).

Example 2225-[5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-{[2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one222 Example 222a5-Bromo-1-methyl-3-(2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one 222a

A mixture of5-bromo-1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one221a (2.75 g, 7.5 mmol), oxetan-3-one (2.5 g, 37.5 mmol), NaBH₃CN (4.75g, 22.5 mmol) and zinc chloride (5 g, 37.5 mmol) in methanol (125 ml)was stirred for 4 hours at room temperature. The mixture was filteredand the filtrate was concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 20:1 DCM/methanol to222a (0.76 g, 25.9%). LC/MS: m/z 392 (M+H)⁺.

Example 222b[4-Fluoro-2-(4-methyl-6-{[2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 222b

A 250 mL round bottomed flask with a magnetic stirrer was charged with222a (0.31 g, 0.8 mmol),(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methylacetate 212b (0.4 g, 0.8 mmol), potassium phosphate (0.43 g, 1.6 mmol),sodium acetate (0.13 g, 1.6 mmol), acetonitrile (30 mL), water (2 mL),and 1,1′-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloridedichloromethane (0.07 g, 0.08 mmol). The reaction mixture was refluxedfor overnight under argon atmosphere. After this time, the mixture wascooled to room temperature and filtered. The filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with 40:1 methylene chloride/methanol to give222b (0.491 g, 89.3%). LC/MS: m/z 684(M+H)⁺

A 25 mL round bottomed flask with a magnetic stirrer was charged with222b (0.471 g, 0.69 mmol), LiOH (1.45 g, 34.5 mmol), THF (10 mL),isopropanol (10 mL) and water (5 mL). The reaction mixture was stirredat room temperature for 30 minutes and filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified byprep-HPLC to give 222 as a white solid (20 mg, 11%). LC/MS: m/z 642(M+H)⁺. ¹H NMR (500 MHz, DMSO) δ 9.14 (s, 1H), 7.82 (s, 1H), 7.63 (d,J=8.5, 1H), 7.51 (s, 1H), 7.39 (d, J=10, 1H), 7.30 (d, J=6.5, 1H), 6.97(d, J=8.5, 1H), 4.86 (m, 1H), 4.84 (m, 2H), 4.51 (m, 3H), 4.41 (m, 1H),4.05 (m, 1H), 3.87 (m, 1H), 3.55 (m, 5H), 2.88 (m, 1H), 2.77 (m, 1H),2.53 (m, 4H), 1.80 (m, 4H), 1.23 (m, 2H).

Example 2235-[5-Fluoro-2-(hydroxymethyl)-3-{1-methyl-5-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one223 Example 223a(4-Fluoro-2-{1-methyl-5-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl)methylAcetate 223a

Following the procedures as described for 136e and starting with5-bromo-1-methyl-3-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridine-2(1H)-one205b and(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 212b, compound 223a was obtained in 50% yield.

Following the procedures as described for compound 136f and startingwith 223a, compound 223 was obtained in 33% yield. LCMS: (M+H)⁺ 600. ¹HNMR (500 MHz, MEOD) δ 8.87 (d, J=2, 1H), 7.40 (d, J=2.5, 1H), 7.35 (d,J=8, 1H), 7.23 (s, 1H), 7.21 (s, 1H), 6.88 (d, J=8, 1H), 4.56 (m, 2H),4.16 (m, 1H), 4.01 (m, 1H), 3.72 (s, 3H), 3.57 (s, 2H), 3.05 (m, 1H),2.95 (m, 3H), 2.84 (m, 4H), 2.59 (m, 2H), 2.49 (s, 3H), 1.90 (m, 4H).

Example 22410-[5-Fluoro-2-(hydroxymethyl)-3-{1-methyl-5-[(5-{[methyl(propan-2-yl)amino]methyl}pyridine-2-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one224 Example 224a10-[5-Fluoro-2-(acetoxymethyl)-3-{1-methyl-5-[(5-{[methyl(propan-2-yl)amino]methyl}pyridine-2-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one224a

Following Example 186f, 186e (365 mg, 0.64 mmol) and 189 (230 mg, 0.51mmol) were reacted to give 224a (80 mg, 20% yield).

Following Example 186, 224a (80 mg, 0.12 mmol), 1N LiOH (0.61 mL), THF(2 mL) and isopropanol (2 mL) were reacted and triturated with EtOAc togive 224 (57 mg, 76% yield). MS (ESI+) m/z 613.6 (M+H).

Example 2252-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one225

Using the same general procedure as described for 118, reaction of 112a(200 mg, 0.706 mmol) and 118f (330 mg, 0.710 mmol) afforded a 17% yield(60 mg) of 225 as a green-yellow solid: mp 199-200° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 11.69 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.41 (t, 1H, J=8.0Hz), 7.25 (d, 3H, J=8.5 Hz), 6.00 (s, 1H), 5.86 (s, 1H), 4.69 (br s,1H), 4.31 (m, 2H), 3.97 (m, 1H), 3.91 (m, 1H), 3.79 (m, 2H), 3.56 (s,3H), 3.01 (m, 1H), 2.90 (m, 1H), 2.70 (m, 2H), 2.15 (s, 3H), 1.90 (m,2H), 1.74 (m, 2H); MS (ESI+) m/z 499.2 (M+H).

Example 2262-(2-(Hydroxymethyl)-3-(1-methyl-6-oxo-5-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one226 Example 226a tert-Butyl7-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate226a

A 100-mL three-neck round-bottomed flask equipped with a magneticstirrer, nitrogen inlet and reflux condenser was charged with3,5-dibromo-1-methylpyridin-2(1H)-one (536 mg, 2.01 mmol), tert-butyl7-amino-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (500 mg, 2.01mmol), cesium carbonate (1.44 g, 4.40 mmol) and 1,4-dioxane (30 mL).After bubbling nitrogen through the resulting mixture for 20 minutes,Xantphos (98.4 mg, 0.170 mmol) andtris(dibenzylideneacetone)dipalladium(0) (91.6 mg, 0.100 mmol) wereadded, and the reaction mixture was heated at 100° C. for 6 h. Afterthis time, the reaction was cooled to room temperature, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography to afford a 96% yield (840 mg) of 226a as ayellow solid: mp 126-128° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, 1H,J=2.5 Hz), 8.10 (s, 1H), 7.79 (s, 1H), 6.95 (d, 1H, J=2.5 Hz), 6.55 (s,1H), 4.53 (s, 2H), 3.64 (t, 2H, J=5.0 Hz), 3.59 (s, 3H), 2.77 (t, 2H,J=5.0 Hz), 1.49 (s, 9H); MS (ESI+) m/z 435.0 (M+H).

Example 226b5-Bromo-1-methyl-3-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylamino)pyridin-2(1H)-one226b

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 226a (840 mg, 1.94mmol) and methylene chloride (12 mL). Trifluoroacetic acid (6 mL) wasadded. The reaction was stirred at room temperature for 2 h. After thistime, the reaction mixture was evaporated under reduced pressure. Theresidue 226b was directly used in the following step.

A 100-mL three-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with ½ of the amount of crude226b prepared above (0.898 mmol presumed), 118f (416 mg, 0.898 mmol),sodium carbonate (381 mg, 3.59 mmol), water (4 mL) and 1,4-dioxane (20mL). After bubbling nitrogen through the resulting suspension for 20min, tetrakis(triphenylphosphine)-palladium(0) (104 mg, 0.090 mmol) wasadded, and the reaction mixture was heated at 100° C. for 4 h. Afterthis time, the reaction mixture was cooled to room temperature andfiltered, and the filter cake was washed with a 1:10 mixture of methanoland methylene chloride (30 mL). The filtrate was concentrated underreduced pressure to afford a brown residue. Another 50-mL single-neckround-bottomed flask equipped with a magnetic stirrer and refluxcondenser was charged with residue obtained above, THF (10 mL), ethanol(10 mL), water (10 mL) and lithium hydroxide (86.0 mg, 3.59 mmol). Themixture was stirred at 50° C. for 2 h. After this time, the reactionmixture was concentrated under reduced pressure. The resulting residuewas purified by flash chromatography to afford a 7.7% (38 mg) yield of226 as an off-white solid: mp 197-199° C.; ¹H NMR (500 MHz, DMSO-d₆) δ8.53 (d, 1H, J=2.0 Hz), 8.23 (s, 1H), 7.90 (s, 1H), 7.43 (t, 1H, J=7.5Hz), 7.35 (d, 1H, J=2.0 Hz), 7.28 (s, 1H), 7.27 (s, 1H), 6.93 (s, 1H),6.00 (s, 1H), 4.72 (t, 1H, J=5.0 Hz), 4.32 (d, 2H, J=5.0 Hz), 3.96 (m,1H), 3.90 (m, 1H), 3.82 (m, 2H), 3.75 (s, 2H), 3.58 (s, 3H), 3.00 (m,1H), 2.94 (m, 1H), 2.90 (t, 2H, J=5.0 Hz), 2.70 (m, 2H), 2.56 (m, 2H),1.92 (m, 2H), 1.76 (m, 2H); MS (ESI+) m/z 551.2 (M+H).

Example 2272-(3-(5-(5-(Azetidin-3-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one227

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 155n (312 mg, 0.931 mmol),118f (472 mg, 1.12 mmol), sodium carbonate (296 mg, 2.79 mmol), DMF (2mL), water (2 mL) and 1,4-dioxane (10 mL). After bubbling nitrogenthrough the resulting suspension for 30 min,tetrakis-(triphenylphosphine)palladium(0) (215 mg, 0.186 mmol) wasadded. A reflux condenser was attached to the flask, and the reactionmixture was heated at 100° C. for 14 h. After this time, the mixture wasdiluted with 90:10 methylene chloride/methanol (100 mL) and water (75mL), and the layers were separated. The aqueous layer was extracted with90:10 methylene chloride/methanol (2×50 mL), and the combined organiclayers were washed with brine (100 mL) and dried over sodium sulfate.The drying agent was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the resulting residue wasdissolved in a mixture of THF (5 mL), water (5 mL) and methanol (5 mL).Lithium hydroxide monohydrate (195 mg, 4.66 mmol) was added, and themixture was stirred at room temperature for 3 h. After this time, themixture was diluted with 90:10 methylene chloride/methanol (100 mL) andwater (50 mL), and the layers were separated. The aqueous layer wasextracted with 90:10 methylene chloride/methanol (2×75 mL), and thecombined organic layers were washed with brine (100 mL) and dried oversodium sulfate. The drying agent was removed by filtration. The filtratewas concentrated under reduced pressure, and the resulting residue waspurified by flash column chromatography (silica, 90:10 methylenechloride/methanol) to afford 227 in 7% yield (36 mg) as an amorphousoff-white solid: mp 227-229° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.66 (d,J=1.5 Hz, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.44(t, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.29 (m, 3H), 6.01 (s, 1H), 4.72 (t,J=4.5 Hz, 1H), 4.33 (s, 2H), 3.99-3.88 (m, 3H), 3.84-3.75 (m, 2H), 3.59(m, 3H), 3.51 (m, 5H), 3.02-2.91 (m, 2H), 2.72 (t, J=5.5 Hz, 2H), 1.92(t, J=5.0 Hz, 2H), 1.77-1.73 (m, 2H); MS (ESI+) m/z 551.2 (M+H).

Example 2282-(2-(Hydroxymethyl)-3-(4-methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one228

Using the same general procedure as described for the preparation of226, reaction of 153a (400 mg, 1.19 mmol) with 118f (718 mg, 1.55 mmol)followed by hydrolysis gave a 12% yield (88 mg) of 228 as a white solid:mp 218-220° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (s, 1H), 7.73 (s, 1H),7.63 (dd, 1H, J=7.5, 2.0 Hz), 7.52 (dd, 1H, J=7.5, 2.0 Hz), 7.43 (t, 2H,J=8.0 Hz), 7.25 (dd, 1H, J=7.5, 1.0 Hz), 6.90 (d, 1H, J=8.0 Hz), 6.00(s, 1H), 4.71 (dd, 1H, J=7.0, 3.5 Hz), 4.46 (m, 2H), 3.94 (m, 2H), 3.82(m, 2H), 3.77 (s, 2H), 3.54 (s, 3H), 3.00 (m, 1H), 2.93 (m, 1H), 2.90(t, 2H, J=5.0 Hz), 2.70 (t, 2H, J=6.0 Hz), 2.62 (t, 2H, J=6.0 Hz), 2.45(m, 1H), 1.92 (m, 2H), 1.76 (m, 2H); MS (ESI+) m/z 551.2 (M+H).

Example 2292-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one229 Example 229a5-Bromo-1-methyl-3-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)pyridin-2(1H)-one229a

Using the same general procedure as described for the preparation of226b, reaction of 3,5-dibromo-1-methylpyridin-2(1H)-one (1.51 g, 5.65mmol) with 5-(1-methylpyrrolidin-2-yl)-2-amino pyridine (1.00 g, 5.65mmol) gave an 81% yield (1.65 g) of 229a as a yellow solid: mp 143-145°C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.68 (d, 1H, J=2.4 Hz),8.15 (d, 1H, J=2.1 Hz), 7.55 (dd, 1H, J=8.9, 2.1 Hz), 7.52 (s, 1H), 7.30(d, 1H, J=8.9 Hz), 3.52 (s, 3H), 3.13 (t, 1H, J=7.5 Hz), 2.99 (t, 1H,J=7.5 Hz), 2.19 (m, 1H), 2.10 (m, 1H), 2.05 (s, 3H), 1.79 (m, 2H), 1.71(m, 1H); MS (ESI+) m/z 363.3 (M+H).

Using the same general procedure as described for the preparation of226, reaction of 229a (500 mg, 1.38 mmol) with 118f (705 mg, 1.52 mmol)followed by a hydrolysis gave a 27% yield (215 mg) of 229 as a whitesolid: mp 146-148° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (dd, 1H, J=2.0Hz), 8.52 (s, 1H), 8.05 (s, 1H), 7.53 (dd, 1H, J=8.5, 2.5 Hz), 7.44 (t,1H, J=8.0 Hz), 7.39 (d, 1H, J=2.5 Hz), 7.29-7.24 (m, 3H), 6.00 (s, 1H),4.72 (t, 1H, J=5.0 Hz), 4.32 (d, 2H, J=5.0 Hz), 3.99 (m, 1H), 3.90 (m,1H), 3.81 (m, 2H), 3.58 (s, 3H), 3.11 (t, 1H, J=8.0 Hz), 3.00 (m, 1H),2.93 (m, 2H), 2.71 (t, 2H, J=6.0 Hz), 2.17 (q, 1H, J=9.0 Hz), 2.06 (m,1H), 2.03 (s, 3H), 1.92 (t, 2H, J=6.0 Hz), 1.83-1.72 (m, 4H), 1.59 (m,1H); MS (ESI+) m/z 579.2 (M+H).

Example 23010-[3-(5-{[5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one230 Example 230a2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-fluoro-6-(9-oxo-4,4-dimethyl-1,10diazatricyclo[6.4.0.0^(2,6)]-dodeca-2(6),7-dien-10-yl)benzylAcetate 230a

Following Example 211d,2-Bromo-4-fluoro-6-(9-oxo-4,4-dimethyl-1,10diazatricyclo[6.4.0.0^(2,6)]-dodeca-2(6),7-dien-10-yl)benzylAcetate 189a (450 mg, 1.0 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (635 mg, 2.5mmol), potassium acetate (393 mg, 4.0 mmol),bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex withCH₂Cl₂ (Pd Cl₂dppf:CH₂Cl₂ (1:1), 66 mg, 0.08 mmol) and 1,4-dioxane (20mL) were heated at 100° C. for 5 h. The reaction mixture was cooled toroom temperature and filtered through a pad of Celite 521. The filtercake was washed with Ethyl Acetate (2×25 mL), and the combined filtrateswere concentrated to dryness under reduced pressure to afford compound230a (quantitative yield) as black oil, which was used directly for thenext step. MS (ESI+) m/z 497.3 (M+H).

Example 230b10-[3-(5-{[5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(acetoxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one230b

Example 230b was synthesized using the same procedure as 121b, exceptusing compound 230a (223 mg, 0.45 mmol),3-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one(200c) (160 mg, 0.45 mmol), 1M sodium carbonate solution (1.5 mL, 1.5mmol), tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.022 mmol) and1,2-dimethoxyethane (4.5 mL). The reaction mixture was heated at 130° C.for 15 minutes in the microwave reactor. Work-up and flash columnchromatography (silica, 9:1 methylene chloride/methanol) give a 43%yield (120 mg) of compound 230b as brown oil: MS (ESI+) m/z 643.1 (M+H).

Following the same procedure as 121, except using a mixture of THF (1mL), water (0.5 mL) and isopropanol (1 mL), compound 230b (120 mg, 0.2mmol) and lithium hydroxide monohydrate (50 mg, 1.2 mmol) were reacted.Work-up and flash column chromatography (NH-silica, ethylacetate/hexanes) give a 30% yield (36 mg) of compound 230 as a lightgreen solid: MS (ESI+) m/z 600.6 (M+H).

Example 2312-(5-fluoro-2-(hydroxymethyl)-3-(4-methyl-6-(2-methylisoindolin-5-ylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one231 Example 231a 5-Nitroisoindoline 231a

To the suspension of isoindoline (2 g, 16.8 mmol) in 98% H₂SO₄ (10 mL)was added dropwise the mixture of concentrated nitric acid (2 mL) and98% sulfuric acid (2 mL) at 0° C. The mixture was stirred at 0° C. for45 minutes. The resulting yellow solution was then poured into icewater. The white solid precipitate was collected by filtration. Thesolid was washed with water (20 mL×2) and dried in vacuum to afford 231aas a white solid (700 mg, 51%). MS: [M+H]+ 165.

Example 231b tert-Butyl 5-Nitroisoindoline-2-carboxylate 231b

The mixture of 5-nitroisoindoline (600 mg, 3.66 mmol) and (Boc)₂O (1.6g, 7.31 mmol) in THF (30 mL) was stirred at room temperature for 2 h.The resulting red solution was then concentrated under reduced pressureand the residue was purified by flash column chromatography eluting with5:1 petroleum ether/ethyl acetate to afford 231b as a yellow solid (750mg, 80%). MS: [M+H]⁺ 209.

Example 231c tert-Butyl 5-Aminoisoindoline-2-carboxylate 231c

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with tert-butyl 5-nitroisoindoline-2-carboxylate(650 mg, 2.5 mmol) and C₂H₅OH (50 mL). This solution was hydrogenatedwith Pd/C (160 mg) at room temperature for 15 h. It was then filteredand the filtrate was concentrated under reduced pressure to afford 231cas a yellow oil (585 mg, 99%), which was used in the next step withoutfurther purification. MS: [M+H]⁺ 179.

Example 231d tert-Butyl5-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)isoindoline-2-carboxylate231d

Following the procedures as described for 129a and starting with 600 mgof tert-butyl 5-aminoisoindoline-2-carboxylate (231c) and 685 mg of3,5-dibromo-1-methylpyrazin-2(1H)-one, 231d was obtained as a yellowsolid (732 mg, 68%). MS: [M+H]⁺ 421.

Example 231e 5-Bromo-3-(isoindolin-5-ylamino)-1-methylpyrazin-2(1H)-one231e

Following the procedures as described for 129b and starting with 460 mgof tert-butyl5-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)isoindoline-2-carboxylate,231e was obtained as a yellow solid (352 mg, 99%). MS: [M+H]⁺ 321

Example 231f5-Bromo-1-methyl-3-(2-methylisoindolin-5-ylamino)pyrazin-2(1H)-one 231f

Following the procedures as described for 220a and starting with 336 mgof 5-bromo-3-(isoindolin-5-ylamino)-1-methylpyrazin-2(1H)-one, compound231f was obtained as a yellow solid (237 mg, 75%). MS: [M+H]⁺ 337. ¹HNMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 7.67 (s, 1H), 7.52 (t, J=7.0, 1H),7.18 (d, J=8.0, 1H), 6.74 (s, 1H), 3.94 (s, 2H), 3.89 (s, 2H), 3.52 (s,3H), 2.60 (s, 3H).

Example 231g4-Fluoro-2-(4-methyl-6-(2-methylisoindolin-5-ylamino)-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 231g

Following the procedures as described for compound 148h and startingwith 400 mg of4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d and 278 mg of5-bromo-1-methyl-3-(2-methylisoindolin-5-ylamino)pyrazin-2(1H)-one 231f,compound 231g was obtained as a yellow solid (258 mg, 51%). MS: [M+H]⁺611.

Following Example 148, 231g was converted to 231 as a white solid (116mg, 50%). ¹H NMR (500 MHz, DMSO) δ 9.23 (s, 1H), 7.90 (s, 1H), 7.73 (d,J=8, 1H), 7.51 (s, 1H), 7.37 (dd, J=10.0, 1H), 7.31 (dd, J=10.0, 1H),7.13 (d, J=8.0, 1H), 6.53 (s, 1H), 4.88 (s, 1H), 4.50 (d, J=8.0, 1H),4.50 (d, J=11.5, 1H), 4.40 (m, 1H), 4.13 (m, 3H), 3.89 (m, 1H), 3.78 (m,4H), 3.52 (s, 3H), 2.59 (m, 2H), 2.48 (m, 5H), 1.79 (s, 2H), 1.70 (s,2H).

Example 2325-[5-fluoro-2-(hydroxymethyl)-3-{4-methyl-6-[(2-methyl-2,3-dihydro-1H-isoindol-5-yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one232 Example 232a(4-Fluoro-2-{4-methyl-6-[(2-methyl-2,3-dihydro-1H-isoindol-5-yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}-6-{6-oxo-8-thia-5azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}phenyl)methylAcetate 232a

Following the procedures as described for 148h and starting with 499 mgof(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 212b and 335 mg of5-bromo-1-methyl-3-(2-methylisoindolin-5-ylamino)pyrazin-2(1H)-one,compound 232a was obtained as a yellow solid (320 mg, 51%). MS: [M+H]⁺628.

Following the procedures as described for 148 and starting with 300 mgof 232a, compound 232 was obtained as a white solid (117 mg, 42%). ¹HNMR (500 MHz, DMSO) δ 9.23 (s, 1H), 7.90 (s, 1H), 7.72 (s, 1H), 7.51 (d,J=8.0, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 7.13 (s, 1H), 4.85 (s, 1H), 4.50(s, 1H), 4.40 (m, 1H), 4.05 (s, 1H), 3.87 (s, 1H), 3.78 (d, J=6.5, 4H),3.56 (s, 3H), 3.33 (s, 3H), 2.97 (s, 1H), 2.87 (s, 1H), 2.79 (s, 2H),2.50 (m, 3H), 1.80 (s, 4H).

Example 2335-[3-(5-{[5-(1-Ethylazetidin-3-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one233 Example 233a[2-(5-{[5-(1-Ethylazetidin-3-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 233a

Following the procedures as described for 136e and starting with5-bromo-3-(5-(1-ethylazetidin-3-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one(250a) and(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 212b, compound 233a was obtained in 67% yield. LCMS: (M+H)⁺ 597

Following the procedures as described for 136 and starting with 233a,compound 233 was obtained in 58% yield. LCMS: (M+H)⁺ 614. ¹H NMR (500MHz, DMSO) δ 8.66 (d, J=2, 1H), 8.56 (s, 1H), 8.11 (d, J=2, 1H), 7.65(dd, J=9, 1H), 7.41 (d, J=2, 1H), 7.33 (dd, J=9.5, 1H), 7.28 (d, J=8,1H), 7.18 (dd, J=9, 1H), 4.86 (t, J=4, 1H), 4.32 (d, J=4.5, 2H), 4.05(m, 1H), 3.86 (m, 1H), 3.59 (s, 3H), 3.49 (m, 3H), 2.97 (m, 3H), 2.86(m, 1H), 2.78 (m, 2H), 2.56 (m, 1H), 2.40 (m, 2H), 1.79 (m, 4H), 0.87(t, J=7, 3H).

Example 2342-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one234 Example 234a{4-Fluoro-2-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-6-{1-oxo-1H,2H,3H,4H,-6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl}methylAcetate 234a

A 25 mL sealed tube was charged with4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (210d) (500 mg, 1.0 mmol),5-bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one(146a) (350 mg, 1.0 mmol), CH₃COONa (170 mg, 2.0 mmol), K₃PO₄ (552 mg,2.0 mmol), PdCl₂(dppf) (85 mg, 0.1 mmol) suspended in CH₃CN (25 mL) andH₂O (1 mL). The mixture was heated at 110° C. for 2 hours. It was thenevaporated and the residue was purified by silical-gel column elutingwith 20:1 methylene chloride/methanol to give 234a as a brown solid (400mg, 63%). MS: (M+H)⁺ 614.

A solution of 234a (400 mg, 0.65 mmol) in propan-2-ol (10 mL),tetrahydrofuran (10 mL) and water (2 mL) was added LiOH (1.57 g, 65mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by prep-HPLC to afford 234 as a yellowsolid (119 mg, 32%). MS: (M+H)⁺ 572. ¹H NMR (500 MHz, MEOD) δ 1.78-1.80(t, 2H), 1.89-1.90 (d, 2H), 2.49 (s, 3H), 2.54-2.56 (t, J=6 Hz, 2H),2.64-2.66 (m, 2H), 2.94-2.96 (t, 2H), 3.64 (s, 2H), 3.67 (s, 3H),4.04-4.06 (m, 3H), 4.20 (s, 3H), 4.46-4.51 (m, 2H), 5.89 (s, 1H), 6.72(s, 1H), 7.20-7.22 (d, 2H), 7.26-7.27 (d, 1H), 7.91 (s, 1H).

Example 2355-(5-Fluoro-2-(hydroxymethyl)-3-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)phenyl)-1-methyl-3-(2-methylisoindolin-5-ylamino)pyrazin-2(1H)-one235

A 100-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 231e(150 mg, 0.447 mmol), 131a (340 mg, 0.581 mmol), sodium carbonate (142mg, 1.34 mmol), water (2 mL) and 1,4-dioxane (8 mL). After bubblingnitrogen through the resulting suspension for 30 min,tetrakis-(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) was added,and the reaction mixture was heated at reflux for 2 h. After that time,the mixture was cooled to room temperature and diluted with methylenechloride (100 mL) and water (30 mL). The organic layer was separated,and the aqueous layer was extracted with methylene chloride (3×30 mL).The combined organic layers were dried over sodium sulfate andconcentrated under reduced pressure to afford a brown residue. A 100-mLsingle-neck round-bottomed flask equipped with a magnetic stirrer waspurged with nitrogen and charged with the crude residue, THF (10 mL) anda 1 M solution of tetrabutylammonium fluoride in THF (4.50 mmol, 4.5mL). The resulting mixture was stirred at room temperature for 2 h.After this time, the mixture was diluted with methylene chloride (100mL) and washed with water (30 mL). The organic layer was separated, andthe aqueous layer was extracted with methylene chloride (3×30 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography (silica, 0% to 10% methanol/methylene chloride) to afforda 44% yield (120 mg) of 235 as an off-white solid: mp 218-220° C. (dec);¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (s, 1H), 7.89 (d, 1H, J=1.0 Hz), 7.70(dd, 1H, J=8.1, 2.0 Hz), 7.50 (s, 1H), 7.34 (dd, 1H, J=9.9, 3.0 Hz),7.30 (dd, 1H, J=9.1, 2.5 Hz), 7.13 (d, 1H, J=8.0 Hz), 4.82 (m, 1H), 4.50(m, 1H), 4.04 (m, 1H), 4.04 (m, 1H), 3.84 (m, 1H), 3.75 (m, 4H), 3.54(s, 3H), 3.02 (m, 1H), 2.89 (m, 1H), 2.75 (s, 2H), 2.53 (d, 2H, J=6.5Hz), 2.46 (s, 3H), 1.23 (s, 6H); MS (ESI+) m/z 600.2 (M+H).

Example 2365-(5-Fluoro-2-(hydroxymethyl)-3-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-3-(5-(3-methylazetidin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one236 Example 236a 5-(3-Methylazetidin-1-yl)-2-nitropyridine 236a

A 500-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 3-methylazetidiniumbenzenesulfonate (4.02 g, 17.5 mmol), 2-nitro-5-bromo pyridine (3.56 g,17.5 mmol), cesium carbonate (28.5 g, 87.7 mmol) and 1,4-dioxane (50mL). After bubbling nitrogen through the resulting suspension for 30min, Xantphos (862 mg, 1.50 mmol) andtris(dibenzylidene-acetone)dipalladium(0) (800 mg, 0.900 mmol) wereadded. A reflux condenser was attached to the flask, and the reactionmixture was heated at reflux for 3 h. After this time, the mixture wascooled to room temperature and diluted with 90:10 methylenechloride/methanol (100 mL) and water (75 mL), and the layers wereseparated. The aqueous layer was extracted with 90:10 methylenechloride/methanol (2×50 mL), and the combined organic extracts werewashed with brine and dried over sodium sulfate. The drying agent wasremoved by filtration. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by flash columnchromatography (silica, 0% to 80% ethyl acetate/hexanes) to afford 236ain 69% yield (2.35 g) as an amorphous yellow solid: mp 141-143° C.; ¹HNMR (500 MHz, CDCl₃) δ 8.12 (d, 1H, J=9.0 Hz), 7.60 (d, 1H, J=2.5 Hz),6.66 (dd, 1H, J=9.0, 2.5 Hz), 4.23 (t, 2H, J=8.5 Hz), 3.68 (m, 2H), 2.99(m, 1H), 1.36 (d, 3H, J=7.0 Hz; MS (ESI+) m/z 194.0 (M+H)

Example 236b 5-(3-Methylazetidin-1-yl)pyridin-2-amine 236b

A 250-mL Parr reactor bottle was purged with nitrogen and charged with10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of236a (2.58 g, 13.4 mmol) in a mixture of ethanol (25 mL) and ethylacetate (25 mL). The bottle was attached to a Parr hydrogenator,evacuated, charged with hydrogen gas to a pressure of 50 psi and shakenfor 3 h. After this time, the hydrogen was evacuated, and nitrogen wascharged into the bottle. Celite 521 (3.50 g) was added, and the mixturewas filtered through a pad of Celite 521. The filter cake was washedwith ethanol (2×50 mL), and the combined filtrates were concentrated todryness under reduced pressure to afford a quantitative yield of 236b(2.21 g) as a purple oil: ¹H NMR (500 MHz, DMSO-d₆) δ 7.19 (d, 1H, J=3.0Hz), 6.66 (dd, 1H, J=9.0, 3.0 Hz), 6.36 (d, 1H, J=8.5 Hz), 5.13 (br s,2H), 3.81 (t, 2H, J=7.5 Hz), 3.21 (t, 2H, J=6.5 Hz), 2.70 (m, 1H), 1.18(d, 3H, J=7.0 Hz); MS (ESI+) m/z 164.1 (M+H).

Example 236c5-Bromo-1-methyl-3-(5-(3-methylazetidin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one236c

Using the same procedure as described for the preparation of 121a, areaction of 236b (1.04 g, 6.40 mmol) with3,5-dibromo-1-methylpyridin-2(1H)-one (1.90 g, 7.12 mmol) afforded a 44%yield (980 mg) of 236c as a brown solid: mp 135-136° C.; ¹H NMR (500MHz, DMSO-d₆) δ 8.49 (d, 1H, J=5.5 Hz), 8.42 (s, 1H), 7.50 (d, 1H, J=4.5Hz), 7.41 (d, 1H, J=7.0 Hz), 7.20 (d, 1H, J=14.5 Hz), 6.85 (dd, 1H,J=14.5, 5.0 Hz), 3.91 (m, 2H), 3.49 (s, 3H), 3.34 (m, 2H), 2.75 (m, 1H),1.21 (d, 3H, J=11.5 Hz; MS (ESI+) m/z 350.2 (M+H).

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 236c (140 mg, 0.400 mmol),182c (304 mg, 0.520 mmol), sodium carbonate (130 mg, 1.23 mmol), water(2 mL) and 1,4-dioxane (10 mL). After bubbling nitrogen through theresulting suspension for 30 min,tetrakis(triphenyl-phosphine)palladium(0) (50 mg, 0.043 mmol) was added.A reflux condenser was attached to the flask, and the reaction mixturewas heated at reflux for 2 h. After this time, the mixture was dilutedwith 90:10 methylene chloride/methanol (100 mL) and water (75 mL), andthe layers were separated. The aqueous layer was extracted with 90:10methylene chloride/methanol (2×50 mL), and the combined organic layerswere washed with brine (100 mL) and dried over sodium sulfate. Thedrying agent was removed by filtration. The filtrate was concentratedunder reduced pressure, and the resulting residue was dissolved in THF.A 1 M solution of tetrabutylammonium fluoride in THF (1.20 mL, 1.20mmol) was added, and the mixture was stirred at room temperature for 14h. After this time, the mixture was diluted with 90:10 methylenechloride/methanol (75 mL) and water (50 mL), and the layers wereseparated. The aqueous layer was extracted with 90:10 methylenechloride/methanol (2×50 mL), and the combined organic extracts werewashed with brine (100 mL) and dried over sodium sulfate. The dryingagent was removed by filtration. The filtrate was concentrated underreduced pressure, and the resulting residue was purified by flash columnchromatography (silica, 0% to 10% methylene chloride/methanol) to afford236 in 14% yield (35 mg) as an amorphous brown solid: mp 170-171° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 8.45 (d, 1H, J=2.5 Hz), 8.22 (s, 1H), 7.31 (m,2H), 7.15 (m, 2H), 6.83 (dd, 1H, J=9.0, 3.0 Hz), 4.83 (t, 1H, J=4.5 Hz),4.32 (m, 2H), 4.05 (m, 1H), 3.88 (m, 3H), 3.02 (m, 1H), 2.89 (m, 1H),2.75 (s, 3H), 2.54 (m, 4H); MS (ESI+) m/z 614.3 (M+H).

Example 2376-(3-(5-(4-(Oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-2,3-(5,5-dimethyl-5,6-dihydro-4H-cyclopenta)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one237

A 100-mL three-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 210c (160 mg, 0.382 mmol),182c (300 mg, 0.512 mmol), sodium carbonate (162 mg, 1.53 mmol), water(6 mL) and 1,4-dioxane (30 mL). After bubbling nitrogen through theresulting suspension for 20 min,tetrakis(triphenyl-phosphine)-palladium(0) (44.0 mg, 0.038 mmol) wasadded, and the reaction mixture was heated at 100° C. for 4 h. Afterthis time, the reaction mixture was cooled to room temperature andfiltered, and the filter cake was washed with a 1:10 mixture of methanoland methylene chloride (30 mL). The filtrate was concentrated underreduced pressure to afford a brown residue. Another 50-mL single-neckround-bottomed flask equipped with a magnetic stirrer and refluxcondenser was charged with the residue obtained above,tetrabutylammonium fluoride (1.0 M in THF, 1.54 mL, 1.54 mmol) and THF(10 mL). The mixture was stirred at room temperature for 1.5 h. Afterthis time, the reaction mixture was concentrated under reduced pressure.The resulting residue was purified by flash chromatography to afford a24% (86 mg) yield of 237 as a yellow solid: mp 175-177° C.; ¹H NMR (500MHz, DMSO-d₆) d 8.55 (d, 1H, J=2.0 Hz), 8.36 (s, 1H), 7.86 (d, 1H, J=3.0Hz), 7.35 (m, 3H), 7.22 (d, 1H, J=9.0 Hz), 7.16 (dd, 1H, J=9.0, 3.0 Hz),4.85 (t, 1H, J=5.0 Hz), 4.55 (t, 2H, J=6.5 Hz), 4.45 (t, 2H, J=6.0 Hz),4.32 (m, 2H), 4.04 (m, 1H), 3.86 (m, 1H), 3.58 (s, 3H), 3.44 (m, 1H),3.06 (t, 4H, J=4.5 Hz), 3.03 (m, 1H), 2.89 (m, 1H), 2.75 (s, 2H), 2.52(m, 2H), 2.38 (t, 4H, J=4.5 Hz); MS (ESI+) m/z 685.4 (M+H).

Example 23810-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one238 Example 238a10-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(acetoxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one238a

To a microwave tube equipped with a stirring bar, 189a (381.9 mg, 0.850mmol),3-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(201a) (560 mg, 1.275 mmol), Pd(PPh₃)₄ (49.1 mg, 0.043 mmol), Na₂CO₃aqueous solution (1.0 N, 2.81 mL, 2.81 mmol), 1,2-dimethoxy-ethane (4mL) were added. The mixture was reacted in microwave at 130° C. for 10min. methylene chloride (200 mL) was added and the resulting mixture waswashed with water (30 mL×3), brine (30 mL×1), dried over MgSO₄,filtered, and removed solvent in vacuo. Silica gel column chromatography(methanol:methylene chloride=5:95) gave 238a.

To a round-bottomed flask equipped with a stirring bar, 238a, THF (5mL), i-PrOH (5 mL), H₂O (5 mL), LiOH H₂O (200 mg) were added. Theresulting mixture was stirred at RT for 1 hr. The solvent was removed invacuo and the resulting residue was added to methylene chloride (200mL), the solution was washed with water (30 mL×3), brine (30 mL×1),dried over MgSO₄, filtered, and removed solvent in vacuo. Silica gelcolumn chromatography (MeOH:methylene chloride/10:90) gave 238 53 as apink solid, 143 mg. MS (ESI+) m/z 640.6 (M+H).

Example 2395-(5-Fluoro-2-(hydroxymethyl)-3-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-3-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one239

Using the same procedure as described for 236, a reaction of 220a (165mg, 0.410 mmol) with 182c (312 mg, 0.533 mmol) afforded a 21% yield (57mg) of 239 as an off-white solid: mp 191-192° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 8.54 (d, 1H, J=2.0 Hz), 8.34 (s, 1H), 7.85 (d, 1H, J=3.0 Hz),7.33 (m, 3H), 7.20 (d, 1H, J=9.0 Hz), 7.15 (dd, 1H, J=9.0, 3.0 Hz), 4.84(t, 1H, J=4.0 Hz), 4.32 (m, 2H), 4.04 (m, 1H), 3.84 (m, 1H), 3.57 (s,3H), 3.02 (m, 5H), 2.87 (m, 1H), 2.75 (br s, 2H), 2.63 (m, 1H), 2.55 (m,6H), 1.22 (s, 6H), 0.98 (d, 6H, J=3.0 Hz); MS (ESI+) m/z 671.3 (M+H).

Example 2405-(3-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-1-methyl-3-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one240

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with182c (300 mg, 0.513 mmol), 205b (138 mg, 0.394 mmol), sodium carbonate(125 mg, 1.18 mmol), 1,4-dioxane (8 mL) and water (2 mL). This mixturewas degassed with nitrogen for 30 min.Tetrakis(triphenylphosphine)palladium (46 mg, 0.039 mmol) was added.After heating at reflux for 2 h, the reaction mixture was cooled to roomtemperature and partitioned between water (40 mL) and methylene chloride(100 mL). The layers were separated, and the aqueous phase was extractedwith methylene chloride (2×50 mL). The organic extracts were combined,dried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was dissolved in THF (3 mL), andtetrabuty-ammonium fluoride trihydrate (372 mg, 1.18 mmol) was added.After stirring at room temperature for 2 h, the reaction mixture waspartitioned between water (20 mL) and methylene chloride (20 mL). Thelayers were separated, and the aqueous phase was extracted withmethylene chloride (2×20 mL). The organic extracts were combined, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by flash chromatography to afford 240in 22% yield (53 mg) as a yellow solid: mp 142-143° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 8.77 (d, 1H, J=2.0 Hz), 8.43 (s, 1H), 7.44 (d, 1H, J=2.0 Hz),7.31 (dd, 1H, J=9.5, 2.5 Hz), 7.27 (d, 1H, J=8.0 Hz), 7.19 (dd, 1H,J=9.5, 2.5 Hz), 7.06 (d, 1H, J=8.0 Hz), 4.86 (m, 1H), 4.38 (m, 2H), 4.04(m, 1H), 3.84 (m, 1H), 3.59 (s, 3H), 3.38 (s, 2H), 3.03 (m, 1H), 2.89(m, 1H), 2.75 (s, 4H), 2.62 (m, 2H), 2.53 (m, 2H), 2.34 (s, 3H), 1.23(s, 6H); MS (ESI+) m/z 614.3 (M+H).

Example 2415-(3-(6,6-Dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-1-methyl-3-(6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one241

Using the same general procedure as described for the preparation of240, reaction of5-bromo-3-(6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1-methylpyridin-2(1H)-one(143 mg, 0.394 mmol) with 182c (300 mg, 0.513 mmol) gave a 28% yield (70mg) of 241 as a yellow solid: mp 134-135° C.; ¹H NMR (500 MHz, DMSO-d₆)δ 8.78 (d, 1H, J=2.0 Hz), 8.43 (s, 1H), 7.44 (d, 1H, J=2.0 Hz), 7.31(dd, 1H, J=9.5, 2.5 Hz), 7.28 (d, 1H, J=8.0 Hz), 7.18 (dd, 1H, J=9.5,2.5 Hz), 7.06 (d, 1H, J=8.0 Hz), 4.86 (m, 1H), 4.38 (m, 2H), 4.04 (m,1H), 3.84 (m, 1H), 3.59 (s, 3H), 3.43 (s, 2H), 3.03 (m, 1H), 2.89 (m,1H), 2.75 (s, 4H), 2.62 (m, 2H), 2.53 (m, 2H), 2.50 (m, 2H), 1.23 (s,6H), 1.08 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 628 (M+H).

Example 2425-[5-Fluoro-2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-3-{[5-(1-methylpiperidin-4-yl)pyridine-2-yl]amino}-1,2-dihydropyridin-2-one242 Example 242a4-Fluoro-2-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 242a

To a microwave tube equipped with a stirring bar,5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one(130c) (240 mg, 0.636 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (336 mg, 0.763 mmol), Pd(PPh₃)₄(37 mg, 0.0318 mmol), Na₂CO₃aqueous solution (1.0 N, 2.1 mL, 2.1 mmol), 1,2-dimethoxyethane (4.2 mL)were added. The mixture was reacted in microwave at 130° C. for 10 min.methylene chloride (200 mL) was added and the resulting mixture waswashed with water (3×30 mL), brine (30 mL), dried over MgSO₄, filtered,and removed solvent in vacuo. Silica gel column chromatography(methanol:methylene chloride=5:95) gave 242a.

To a round-bottomed flask equipped with a stirring bar, 242a, THF (5mL), i-PrOH (5 mL), H₂O (5 mL), LiOH H₂O (300 mg) were added. Theresulting mixture was stirred at RT for 1 hr. Removed all the solvent invacuo and the resulting residue was added to methylene chloride (200mL), the solution was washed with water (30 mL×3), brine (30 mL×1),dried over MgSO₄, filtered, and removed solvent in vacuo. Silica gelcolumn chromatography (MeOH: methylene chloride=10:90) gave 242 as abrown solid, 56 mg. MS (ESI+) m/z 611.5 (M+H).

Example 24310-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylpyrrolidin-2-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one243 Example 243a10-[5-Fluoro-2-(acetoxymethyl)-3-(1-methyl-5-{[5-(1-methylpyrrolidin-2-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one243a

Example 243a was synthesized using the same procedure as 121b, exceptusing compound 230a (446 mg, 0.9 mmol),5-bromo-1-methyl-3-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)pyridin-2(1H)-one(229a) (281 mg, 0.8 mmol), 1M sodium carbonate solution (2.7 mL, 2.7mmol), tetrakis(triphenylphosphine)-palladium(0) (47 mg, 0.040 mmol) and1,2-dimethoxyethane (6.5 mL). The reaction mixture was heated at 130° C.for 15 minutes in the microwave reactor. Work-up and flash columnchromato-graphy (silica, 9:1 methylene chloride/methanol) give a 67%yield (350 mg) of 243a as brown oil: MS (ESI+) m/z 653.1 (M+H).

Following Example 121, except using a mixture of THF (2 mL), water (1mL) and isopropanol (2 mL), compound 243a (350 mg, 0.54 mmol) andlithium hydroxide monohydrate (150 mg, 3.5 mmol). Work-up and flashcolumn chromatography (NH-silica, ethyl acetate/hexanes) give a 29%yield (95 mg) of compound 243 as a pale yellow solid: MS (ESI+) m/z611.5 (M+H).

Example 24410-[5-Fluoro-2-(hydroxymethyl)-3-[4-methyl-6-({4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one244 Example 244a10-[5-Fluoro-2-(acetoxymethyl)-3-[4-methyl-6-({4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one244a

Following Example 121b, except using compound 230a (188 mg, 0.38 mmol),5-bromo-1-methyl-3-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)pyrazin-2(1H)-one214b (160 mg, 0.38 mmol), 1M sodium carbonate solution (1.5 mL, 1.5mmol), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol) and1,2-dimethoxyethane (5 mL). The reaction mixture was heated at 130° C.for 15 minutes in the microwave reactor. Work-up and flash columnchromatography (silica, 60:35:5 methylene chloride/diethylether/methanol) give a mixture (270 mg) of compound 244a and 244 asyellow oil.

The mixture from 244a (270 mg) was deprotected using the same procedureas 121, except using a mixture of THF (2 mL), water (1 mL) andisopropanol (2 mL) and Lithium hydroxide monohydrate (85 mg, 2 mmol).Work-up and flash column chromatography (NH-silica, ethylacetate/hexanes) give a 63% yield (167 mg) of compound 244 as a paleyellow solid: MS (ESI+) m/z 667.6 (M+H).

Example 24510-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]-pyridin-2-yl}amino)-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one245 Example 245a10-[5-Fluoro-2-(acetoxymethyl)-3-[1-methyl-6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]-pyridin-2-yl}amino)-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one245a

A 44-mL sealed tube equipped with a magnetic stirrer was charged with220a (400 mg, 1.0 mmol), 7 (508 mg, 2.0 mmol), potassium acetate (392mg, 4.0 mmol) and 1,4-dioxane (10 mL). After the mixture was degassedfor 30 minutes, Pd(dppf)Cl₂.CH₂Cl₂ (82 mg, 0.10 mmol) was added. Theresulting reaction mixture was stirred at 105° C. for 6 h. Then, it wascooled to room temperature and filtered through a pad of Celite. Thefiltrate was concentrated, and the crude mixture was redissolved in DME(2 mL) and transferred into a 10-mL microwave reaction vessel. To thissolution was added10-[2-(acetoxymethyl)-3-bromo-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo-[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one(189a) (270 mg, 0.60 mmol), Pd(PPh₃)₄ (50 mg, 0.050 mmol), and 2 NNa₂CO₃ (2 mL). Then, the reaction mixture was degassed for 5 minutes andplaced into the microwave cavity. After the reaction mixture was stirredat 125° C. for 7 min., it was purified by flash chromatography(dichloromethane:methanol, 85:15) to give 49% (150 mg) of 245a.

A 100-mL, single-necked, round-bottomed flask equipped with a magneticstirring bar was charged with 245a (150 mg, 0.22 mmol), LiOH.H₂O (100mg, 2.2 mmol), THF (2 mL), isopropanol (2 mL), and water (2 mL). Afterthe reaction mixture was stirred at room temperature for 3 h, it waspartitioned between dichloromethane (5 mL) and water (5 mL), and theorganic phase was extracted with dichloromethane (5 mL×3). The combinedorganic phases were washed with water (5 mL×2) and brine (5 mL×1), dried(Na₂SO₄), and concentrated. The crude product was re-dissolved indichloromethane (3 mL). To this solution was added hexane (10 mL) andthe resulting precipitates were filtered to give 49% yield (70 mg) of245. MS(ESI⁺) m/z 654.6 (M+H).

Example 24610-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one246 Example 246a10-[5-Fluoro-2-(acetoxymethyl)-3-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one246a

A microwave tube equipped with a magnetic stirrer was charged with5-bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one146a (210 mg, 0.6 mmol), 230a (460 mg, 0.9 mmol), 1,2-dimethoxyethane (8mL) and 1M aqueous sodium carbonate (2 mL). After bubbling N₂ for 15min, Pd(PPh₃)₄ (36 mg, 0.03 mmol) was added. The mixture was heated inmicrowave to 135° C. for 15 min. After this time, ethyl acetate (5 mL)and water (5 mL) were added. The separated aqueous layer was extractedwith ethyl acetate (2×5 mL). The combined organics were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography eluting with a gradient of methylene chloride—60:35:5methylene chloride/diethyl ether/methanol to afford a 37% yield (140 mg)of 246a.

A 25 mL round bottom flask with a magnetic stirrer was charged with 246a(140 mg, 0.2 mmol), lithium hydroxide (200 mg, 4.8 mmol), THF (3 mL),isopropanol (3 mL) and water (2 mL). The mixture stirred at rt for 1 h.After this time, ethyl acetate (5 mL) and water (5 mL) were added. Theseparated aqueous layer was extracted with ethyl acetate (2×5 mL). Thecombined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography using the Biotage KPNH12+M column eluting with a gradient of hexanes—ethyl acetate to afford a86% yield (120 mg) of 246. MS (ESI+) m/z 586.6 (M+H).

Example 24710-[5-Fluoro-2-(hydroxymethyl)-3-{4-methyl-6-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one247 Example 247a(2-Bromo-6-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluorophenyl)methylAcetate 247a

A mixture of4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one(105h) (2 g, 9.05 mmol), 2,6-dibromo-4-fluorobenzyl acetate (197c)(8.8g, 27.15 mmol), XantPhos (524 mg, 0.9 mmol), Pd₂(dba)₃ (828 mg, 0.9mmol) and Cs₂CO₃ (5.9 g, 18 mmol) in dioxane (200 mL) was heated at 100°C. for 15 h under nitrogen. The reaction mixture was filtered and thefiltrated was evaporated in vacuo. The residue was purified bysilical-gel column eluting with 1:1 ethyl acetate/petroleum ether togive 247a as a yellow solid (3 g, 71%). MS: (M+H)⁺ 466.

Example 247b(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylAcetate 247b

A solution of 247a (3 g, 6.45 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (9.8 g, 38.7mmol) in dioxane (160 mL) was added PdCl₂(dppf) (525 mg, 0.65 mmol) andCH₃COOK (3.8 g, 38.7 mmol). The mixture was stirred at 100° C. for 15 hunder argon atmosphere. After reaction the mixture was filtered andevaporated in vacuo and the residue was purified by silical-gel columneluting with 1:2 ethyl acetate/petroleum ether to give 247b as a yellowsolid (2.5 g, 76%). MS: (M+H)⁺ 514.

Example 247c(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-{4-methyl-6-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl)methylAcetate 247c

A 25 mL sealed tube was charged with 247b (590 mg, 1.15 mmol),5-bromo-1-methyl-3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one221b (400 mg, 1.15 mmol), CH₃COONa (189 mg, 2.3 mmol), K₃PO₄ (611 mg,2.3 mmol), PdCl₂(dppf) (94 mg, 0.11 mmol) suspended in CH₃CN (25 mL) andwater (1 mL). The mixture was heated at 110° C. for 2 hours. The mixturewas evaporated and the residue was purified by silical-gel columneluting with 20:1 methylene chloride/methanol to give 247c as a brownsolid (400 mg, 53%). MS: (M+H)⁺ 656.

A solution of 247c (400 mg, 0.61 mmol) in propan-2-ol (8 mL),tetrahydrofuran (8 mL) and water (1.5 mL) was added LiOH (1.46 g, 61mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by prep-HPLC to afford 247 as a yellowsolid (124 mg, 33%). MS: (M+H)⁺ 614. ¹H NMR (500 MHz, MeOD) δ 1.29 (s,6H), 2.46 (s, 3H), 2.59-2.60 (d, 2H), 2.74-2.76 (t, 2H), 2.81 (s, 2H),2.93-2.98 (m, 3H), 3.07-3.09 (m, 1H), 3.59 (s, 2H), 3.64 (s, 3H),3.95-3.97 (m, 1H), 4.01-4.12 (m, 1H), 4.48-4.51 (d, 1H), 4.58-4.61 (d,1H), 7.03-7.05 (d, 1H), 7.18-7.21 (m, 1H), 7.38-7.41 (m, 2H), 7.52-7.54(d, 1H), 7.64 (s, 1H).

Example 24810-(3-{6-[(2-Ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-5-fluoro-2-(hydroxymethyl)phenyl)-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one248 Example 248a5-Bromo-3-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-1-methylpyrazin-2(1H)-one248a

Following the procedures as described for 220a and starting with 385 mgof5-bromo-1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one(221a), 248a was obtained as yellow solid (292 mg, 70%). MS: [M+H]⁺ 364.

Example 248b2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-6-{6-[(2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-4-fluorophenyl)methylAcetate 248b

Following the procedures as described for 129a and starting with 400 mgof(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate (247b) and 283 mg of5-bromo-3-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-1-methyl-pyrazin-2(1H)-one,248b was obtained as a yellow solid (260 mg, 50%).

Following the procedures as described for 148 and starting with 230 mgof 248b, 127 mg of 248 was obtained as a white solid (59%). ¹H NMR (500MHz, DMSO) δ 9.15 (s, 1H), 7.81 (s, 1H), 7.63 (dd, J=8, 1H), 7.52 (s,1H), 7.39 (dd, J=9.5, 1H), 7.31 (d, J=9.5, 1H), 6.97 (d, J=8.0, 1H),4.88 (s, 1H), 4.50 (s, 1H), 4.45 (s, 1H), 4.04 (m, 1H), 3.84 (m, 1H),3.54 (s, 3H), 3.47 (s, 2H), 3.03 (m, 1H), 2.91 (m, 1H), 2.76 (s, 3H),2.62-2.45 (m, 6H), 1.23 (s, 6H), 1.08 (t, J=7.5, 3H).

Example 24910-[5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-{[2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one249 Example 249a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4-methyl-6-{[2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)methylAcetate 249a

Following the procedures as described for 148b and starting with 247band 305 mg of 222a, 277 mg of 249a was obtained as a yellow solid (51%).MS: [M+H]⁺ 698.

Following the procedures as described for compound 148 and starting with250 mg of 249a, 117 mg of 249 was obtained as a white solid (50%). ¹HNMR (500 MHz, DMSO) δ 9.17 (s, 1H), 7.85 (d, J=1.5, 1H), 7.65 (dd, J=8,1H), 7.52 (s, 1H), 7.39 (dd, J=9.5, 1H), 7.31 (d, J=9.5, 1H), 6.97 (d,J=8.0, 1H), 4.80 (s, 1H), 4.61 (m, 2H), 4.52 (m, 1H), 4.43 (m, 1H), 4.04(m, 1H), 3.85 (m, 1H), 3.56 (m, 4H), 3.34 (s, 2H), 3.01-2.57 (m, 6H),2.53 (m, 5H), 1.23 (s, 6H).

Example 2502-(3-(5-(5-(1-Ethylazetidin-3-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one250 Example 250a5-Bromo-3-(5-(1-ethylazetidin-3-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one250a

To a solution of3-(5-(azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one155n (crude, 4.6 mmol) in methanol (50 mL) and acetic acid (5 mL) at 0°C., was added CH₃CHO (40% wt in H₂O) (10 g, 92 mmol) followed by theaddition of NaBH(CH₃O)₃(20 g, 92 mmol) in small portions over a periodof 1 h. After the reaction was finished, the mixture was adjusted topH>7 with 2N NaOH. Then the mixture was extracted with DCM (80 mL×3),dried over Na₂SO₄ and concentrated to get a yellow solid, which waspurified on flash column eluting with 50:1 DCM/MeOH containing 0.5% Et₃Nto afford 250a as a yellow solid (43%, two steps). LCMS: (M+H)⁺ 364. ¹HNMR (500 MHz, DMSO) δ 8.72 (s, 1H), 8.66 (d, J=3, 1H), 8.21 (d, J=3,1H), 7.68 (dd, J=9, 1H), 7.52 (d, J=2.5, 1H), 7.32 (d, J=9, 1H), 3.54(m, 6H), 2.99 (m, 2H), 2.42 (m, 2H), 0.89 (t, J=7, 3H).

Example 250b2-(5-(5-(1-Ethylazetidin-3-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 250b

Following Example 136e, starting with 250a and4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d, a 65% yield of 250b was obtained. LCMS: (M+H)⁺ 639

Following Example 135, starting with 250b, a 63% yield of 250 wasobtained. LCMS: (M+H)⁺ 597. ¹H NMR (500 MHz, DMSO) δ 8.66 (d, J=2, 1H),8.56 (s, 1H), 8.11 (d, J=1.5, 1H), 7.66 (dd, J=8.5, 1H), 7.42 (d, J=2.5,1H), 7.33 (dd, J=9.5, 1H), 7.28 (d, J=8.5, 1H), 7.19 (dd, J=9, 1H), 6.53(s, 1H), 4.87 (t, J=4, 1H), 4.31 (d, J=4.5, 2H), 4.15 (m, 3H), 3.89 (m,1H), 3.59 (s, 3H), 3.47 (m, 3H), 2.97 (m, 2H), 2.62 (m, 3H), 2.40 (m,3H), 1.79 (m, 2H), 1.69 (m, 2H), 0.88 (t, J=7, 3H).

Example 2515-(5-Fluoro-2-(hydroxymethyl)-3-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)-3-(5-(1-methylazetidin-3-yloxy))-1-methylpyridin-2(1H)-one251 Example 251a tert-Butyl3-(6-Nitropyridin-3-yloxy)azetidine-1-carboxylate 251a

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 2-nitro-5-hydroxypyridine(2.00 g, 14.3 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (6.06 g,21.5 mmol), sodium hydride (800 mg, 20.2 mmol) and DMF (30 mL). Thereaction mixture was heated at 110° C. for 24 h. After this time, thereaction mixture was cooled to room temperature and concentrated underreduced pressure. The residue was diluted with ethyl acetate (200 mL)and washed with saturated aqueous sodium bicarbonate (100 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by flashchromatography to afford 251a in 95% yield (4.00 g) as a yellow oil: ¹HNMR (500 MHz, CDCl₃) δ 8.27 (d, 1H, J=9.0 Hz), 8.14 (d, 1H, J=3.0 Hz),7.26 (dd, 1H, J=9.0, 3.0 Hz), 5.04 (m, 1H), 4.39 (m, 2H), 4.06 (m, 2H),1.44 (s, 9H); MS (ESI+) m/z 196.1 (M-Boc+H).

Example 251b tert-Butyl3-(6-Aminopyridin-3-yloxy)azetidine-1-carboxylate 251b

A 250-mL Parr reactor bottle was purged with nitrogen and charged withplatinum oxide (200 mg), 251a (2.00 g, 6.78 mmol), ethyl acetate (30 mL)and ethanol (30 mL). The bottle was attached to a Parr hydrogenator,evacuated, charged with hydrogen gas to a pressure of 50 psi and shakenfor 20 h. After this time, the hydrogen was evacuated, and nitrogen wascharged into the bottle. Celite 521 (10.0 g) was added, and the mixturewas filtered through a pad of Celite 521. The filter cake was washedwith methanol (2×50 mL), and the combined filtrates were concentrated todryness under reduced pressure to afford a 100% yield (2.01 g) of 251bas a white solid: mp 83-84° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.53 (d, 1H,J=3.0 Hz), 7.04 (dd, 1H, J=9.0, 3.0 Hz), 6.41 (d, 1H, J=9.0 Hz), 5.32(br s, 2H), 4.21 (t, 2H, J=6.5 Hz), 3.75 (t, 2H, J=6.5 Hz), 3.25 (m,1H), 1.37 (s, 9H); MS (ESI+) m/z 266.2 (M+H).

Example 251c tert-Butyl3-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yloxy)azetidine-1-carboxylate251c

Using the same procedure as described for the preparation of 250a,reaction of 251b (1.01 g, 3.80 mmol) with3,5-dibromo-1-methylpyridin-2(1H)-one (1.01 g, 3.80 mmol) afforded an81% yield (1.40 mg) of 251c as a brown solid: mp 120-121° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.57 (d, 1H, J=2.5 Hz), 7.86 (d, 1H,J=3.0 Hz), 7.48 (d, 1H, J=2.5 Hz), 7.35 (d, 1H, J=9.0 Hz), 7.28 (m, 1H),4.95 (m, 1H), 4.3 (m, 2H), 3.80 (m, 2H), 3.50 (s, 3H), 1.38 (s, 9H); MS(ESI+) m/z 452.3 (M+H).

Example 251d3-(5-(Azetidin-3-yloxy)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one251d

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with 251c (1.14 g, 3.10 mmol), methylene chloride(10 mL) and trifluoroacetic acid (5 mL). The reaction mixture wasstirred at room temperature for 2 h. After this time, the mixture wasconcentrated under reduced pressure. The resulting residue was dilutedwith methylene chloride (100 mL) and washed with saturated aqueoussodium bicarbonate (50 mL). The aqueous layer was extracted withmethylene chloride (2×50 mL) and the combined organic extracts weredried over sodium sulfate, filtered and concentrated to afford a 92%yield (1.10 g) of 251d as a colorless oil. This compound was useddirectly for the next step without any purification: ¹H NMR (500 MHz,DMSO-d₆) δ 8.65 (s, 1H), 8.55 (d, 1H, J=2.5 Hz), 7.82 (d, 1H, J=3.0 Hz),7.48 (d, 1H, J=2.5 Hz), 7.30 (d, 1H, J=9.0 Hz), 7.21 (m, 1H), 4.95 (t,1H, J=6.0 Hz), 3.76 (m, 1H), 3.48 (m, 5H); MS (ESI+) m/z 353.0 (M+H).

Example 251e5-Bromo-1-methyl-3-(5-(1-methylazetidin-3-yloxy)pyridin-2-ylamino)pyridin-2(1H)-one251e

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 251d (1.10 g, 2.95mmol), 37% solution of formaldehyde in water (111 mg, 3.70 mmol) andmethanol (15 mL). A suspension of sodium cyanoborohydride (540 mg, 8.60mmol) and zinc chloride (600 mg, 4.40 mmol) in methanol (10 mL) wasadded, and the reaction was stirred at room temperature for 4 h. Afterthis time, the reaction mixture was concentrated, and the residue waspartitioned between 90:10 methylene chloride/methanol (250 mL) and 10%aqueous potassium carbonate (100 mL). The aqueous layer was extractedwith 90:10 methylene chloride/methanol (3×150 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by columnchromatography (silica, 0% to 50% methanol/methylene chloride) to afforda 80% yield (830 mg) of 251e as an brown solid: mp 100-101° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.55 (d, 1H, J=2.5 Hz), 7.86 (d, 1H,J=3.0 Hz), 7.47 (d, 1 h, J=2.5 Hz), 7.31 (d, 1H, J=9.0 Hz), 7.24 (dd,1H, J=9.5, 3.5 Hz), 4.76 (m, 1H), 3.77 (t, 2H, J=7.5 Hz), 3.50 (s, 3H),3.03 (t, 2H, J=7.5 Hz), 2.26 (s, 3H); MS (ESI+) m/z 366.0 (M+H).

Using the same procedure as described for the preparation of 239, areaction of 251e (145 mg, 0.400 mmol) with 182c (304 mg, 0.520 mmol)afforded a 15% yield (37 mg) of 251 as a off-white solid: mp 160-161°C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (d, 1H, J=2.5 Hz), 8.49 (s, 1H),7.77 (d, 1H, J=2.5 Hz), 7.36 (d, 1H, J=2.0 Hz), 7.32 (dd, 1H, J=9.0, 2.5Hz), 7.27 (d, 1H, J=9.0 Hz), 7.22 (dd, 1H, J=9.0, 2.5 Hz), 7.16 (dd, 1H,J=9.0, 2.5 Hz), 4.84 (t, 1H, J=4.0 Hz), 4.69 (m, 1H), 4.30 (m, 2H), 3.84(m, 1H), 3.69 (m, 2H), 3.58 (s, 3H), 3.02 (m, 1H), 2.92 (m, 3H), 2.75(m, 2H), 2.54 (m, 2H), 2.27 (s, 3H); MS (ESI+) m/z 630.3 (M+H).

Example 25210-[5-fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(oxetan-3-yl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one252 Example 252a5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one252a

Following Example 214b,5-bromo-1-methyl-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one126a (250 mg, 0.78 mmol), oxetan-3-one (600 mg, 8.3 mmol) were dissolvedin methanol (8 mL). Sodium cyanoborohydride (148 mg, 3 mmol) and zincchloride (165 mg, 1.5 mmol) in methanol (8 mL) was added, and thereaction was heated at 48° C. for 12 hours. Work-up and flash columnchromatography (silica, 60:35:5 methylene chloride/diethylether/methanol) afford a 34% yield (100 mg) of 252a as a light greensolid: MS (ESI+) m/z 382.1 (M+H).

Following Example 121b, except using 230a (135 mg, 0.26 mmol), 252a (100mg, 0.26 mmol), 1M sodium carbonate solution (1 mL, 1 mmol),tetrakis(tripheny-phosphine)palladium(0) (15 mg, 0.013 mmol) and1,2-dimethoxyethane (2.5 mL). The reaction mixture was heated at 130° C.for 15 minutes in the microwave reactor. Work-up and flash columnchromatography (silica, 60:35:5 methylene chloride/diethylether/methanol) give a mixture (80 mg) of 252b and 252 as yellow oil.This mixture (80 mg) was deprotected using the same procedure 121,except using a mixture of THF (1 mL), water (0.5 mL) and isopropanol (1mL) and Lithium hydroxide monohydrate (25 mg, 0.6 mmol). Work-up andflash column chromatography (NH-silica, Ethyl Acetate/Hexanes) give a40% yield (30 mg) of 252 as a white solid: MS (ESI+) m/z 628.5 (M+H).

Example 2535-[5-Fluoro-2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-3-({5-[(2R)-1-methylpyrrolidin-2-yl]pyridine-2-yl}amino)-1,2-dihydropyridin-2-one253 Example 2545-[5-Fluoro-2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-3-({5-[(2S)-1-methylpyrrolidin-2-yl]pyridine-2-yl}amino)-1,2-dihydropyridin-2-one254

Examples 253 and 254 are enantiomers of racemate 202. The racemicmixture 202 was subjected to chiral separation on a Chiralpak AD, 4.6×50mm, 3 mm column (mobile phase 55% isopropanol (w/0.1% triethylamine)/45%CO₂, flow rate 5 mL/min) at 40° C. to give individual enantiomers, with254 eluting first, followed by 253 last. Examples 253 MS (ESI+) m/z597.4 (M+H). Examples 254 MS (ESI+) m/z 597.4 (M+H).

Example 2555-[5-Fluoro-2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-3-{[5-(morpholin-4-yl)pyridin-2-yl]amino}-1,2-dihydropyridin-2-one255 Example 255a 4-(6-Nitropyridin-3-yl)morpholine 255a

Following the procedures as described for 188a and starting with 2 g of5-bromo-2-nitropyridine and 968 mg morpholine, 255a was obtained as ayellow solid (1 g, 50%). MS: [M+H]⁺ 210. ¹H NMR (500 MHz, CDCl3) δ 8.18(d, J=9.0, 1H), 8.15 (d, J=3.0, 1H), 7.22 (dd, J=3.0, 1H), 3.90 (t,J=5.0, 4H), 3.42 (t, J=5.0, 4H).

Example 255b 5-Morpholinopyridin-2-amine 255b

Following the procedures as described for 188b and starting with 1 g of4-(6-nitropyridin-3-yl)morpholine, 255b was obtained as a yellow solid(840 mg, 98%). MS: [M+H]⁺ 210

Example 255c5-Bromo-1-methyl-3-(5-morpholinopyridin-2-ylamino)pyridin-2(1H)-one 255c

Following the procedures as described for 188c and starting with3,5-dibromo-1-methylpyridin-2(1H)-one (1.15 g, 4.3 mmol) and5-morpholinopyridin-2-amine (770 mg, 4.3 mmol), 255c was obtained as ayellow solid (986 mg, 63%). MS: [M+H]⁺ 365

Example 255d4-Fluoro-2-(1-methyl-5-(5-morpholinopyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 255d

Following the procedures as described for 148c and starting with 400 mgof4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d and 302 mg of5-bromo-1-methyl-3-(5-morpholinopyridin-2-ylamino)pyridin-2(1H)-one,255d was obtained as a yellow solid (281 mg, 53%). MS: [M+H]⁺ 641

Following the procedures as described for 148 and starting with 270 mgof4-fluoro-2-(1-methyl-5-(5-morpholinopyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate, 255 was obtained as a white solid (103 mg, 41%). MS: [M+H]⁺599. ¹H NMR (500 MHz, DMSO) δ 8.56 (d, J=2.0, 1H), 8.38 (s, 1H), 7.87(d, J=3.0, 1H), 7.36-7.32 (m, 3H), 7.25 (d, J=9.5, 2H), 7.19 (d, J=9.0,1H), 6.52 (s, 1H), 4.87 (s, 1H), 4.32 (d, J=4, 2H), 4.15 (m, 3H), 3.82(m, 1H), 3.72 (t, J=4.0, 1H), 3.50 (s, 3H), 3.02 (t, J=4.5, 3H), 2.61(m, 2H), 2.47 (m, 2H), 1.80 (s, 2H), 1.68 (S, 2H).

Example 25610-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(morpholin-4-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one256 Example 256a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(1-methyl-5-{[5-(morpholin-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl)methylAcetate 256a

Following Example 148b, starting with 400 mg of(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b and 284 mg5-bromo-1-methyl-3-(5-morpholinopyridin-2-ylamino)pyridin-2(1H)-one255c, 277 mg of 256a was obtained as a yellow solid (53%). MS: [M+H]⁺672

Following Example 148, starting with 270 mg of 256a, 103 mg of 256 wasobtained as a white solid (41%). MS: [M+H]⁺ 630. ¹H NMR (500 MHz, DMSO)δ 8.56 (d, J=2.0, 1H), 8.38 (s, 1H), 7.88 (d, J=3.0, 1H), 7.36-7.32 (m,3H), 7.25 (d, J=9.5, 2H), 7.19 (d, J=9.0, 1H), 4.85 (s, 1H), 4.32 (d,J=4, 2H), 4.07 (m, 3H), 3.86 (m, 1H), 3.72 (t, J=4.0, 1H), 3.50 (s, 3H),3.02 (t, J=4.5, 3H), 2.89 (m, 1H), 2.76 (s, 2H), 2.53 (m, 2H), 1.23 (s,6H).

Example 25710-[3-(5-{[5-(1-Ethylazetidin-3-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one257 Example 257a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-6-(5-{[5-(1-ethylazetidin-3-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluorophenyl)methylAcetate 257a

Following Example 136a, starting with5-bromo-3-(5-(1-ethylazetidin-3-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one250a and(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b, compound 257a was obtained in 37% yield.

Following Example 136, starting with 257a, compound 257 was obtained in46% yield. LCMS: (M+H)⁺ 628. ¹H NMR (500 MHz, DMSO) δ 8.66 (d, J=2, 1H),8.55 (s, 1H), 8.12 (d, J=2.5, 1H), 7.65 (dd, J=8.5, 1H), 7.42 (d, J=2,1H), 7.33 (dd, J=9.5, 1H), 7.28 (d, J=9, 1H), 7.19 (dd, J=9, 1H), 4.86(t, J=4, 1H), 4.33 (m, 2H), 4.05 (m, 1H), 3.86 (m, 1H), 3.59 (s, 3H),3.49 (m, 3H), 3.04 (m, 1H), 2.97 (m, 2H), 2.89 (m, 1H), 2.76 (s, 2H),2.55 (m, 2H), 2.40 (m, 2H), 1.79 (m, 4H), 1.23 (s, 6H), 0.88 (t, J=7,3H).

Example 2582-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one258 Example 258a tert-Butyl6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate258a

A 100 mL round bottomed flask was charged with tert-butyl6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (2 g, 8 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (1.8 g, 6.7 mmol), cesiumcarbonate (4.4 g, 13.4 mmol), XantPhos (0.41 g, 0.7 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.64 g, 0.7 mmol) and1,4-dioxane (50 mL). The reaction mixture was refluxed under argonatmosphere for 2 h. After this time, the mixture was cooled to roomtemperature and filtered. The filtrate was concentrated under reducedpressure. The residue was purified by column chromatography eluting with25:1 dichloromethane/methanol to give 258a (2.18 g, 63%). LC/MS: m/z 435(M+H)⁺

Example 258b5-Bromo-1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyridine-2(1H)-one258b

Compound 258a (2.18 g, 5 mmol) was suspended in dioxane (10 mL).Saturated hydrogen chloride in dioxane (20 mL) was added dropwise. Thereaction mixture was stirred for 20 minutes and concentrated underreduced pressure to afford 258b, which was used without furtherpurification in the next step. LC/MS: m/z 335 (M+H)⁺

Example 258c5-Bromo-1-methyl-3-(2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyridin-2(1H)-one258c

A mixture of 258b (1.7 g, 5 mmol), oxetan-3-one (1.8 g, 25 mmol),NaBH₃CN (1 g, 15 mmol) and zinc chloride (3.4 g, 25 mmol) in methanol(50 mL) was stirred for 4 hours at room temperature. The mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 25:1dichloromethane/methanol to give 258c (1.8 g, 92%). LC/MS: m/z 391(M+H)⁺

Example 258d4-Fluoro-2-(1-methyl-5-(2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 258d

A 15 mL microwave reaction vial with a magnetic stirrer was charged with258c (0.39 g, 1 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (0.48 g, 1 mmol), potassium phosphate (0.54 g, 2 mmol),sodium acetate (0.17 g, 2 mmol), acetonitrile (10 mL), water (1 mL), and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane (0.08 g, 0.1 mmol). The reaction mixture was heated at110° C. for 2 hours under argon atmosphere. After this time, the mixturewas cooled to room temperature and filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 40:1 dichloromethane/methanol to give 258d(0.3 g, 50%). LC/MS: m/z 666 (M+H)⁺

A 25 mL round bottomed flask with a magnetic stirrer was charged with258d (0.6 g, 0.9 mmol), LiOH (2 g, 48 mmol), THF (5 mL), isopropanol (5mL) and water (2 mL). The reaction mixture was stirred at roomtemperature for 30 minutes and filtered. The filtrate was concentratedunder reduced pressure. The residue was purified by prep-HPLC to give258. LC/MS: m/z 624 (M+H)⁺. ¹H NMR (500 MHz, DMSO) δ 7.62 (s, 1H), 7.82(s, 1H), 7.34 (m, 3H), 7.20 (m, 1H), 7.09 (m, 2H), 6.94 (m, 1H), 4.86(m, 1H), 4.96 (m, 1H), 4.60 (m, 2H), 4.51 (m, 2H), 4.31 (m, 2H), 4.14(m, 3H), 3.87 (m, 1H), 3.58 (m, 4H), 3.33 (m, 3H), 2.75 (m, 2H), 2.60(m, 3H), 2.50 (m, 3H), 1.78 (m, 4H).

Example 2595-[2-(Hydroxymethyl)-3-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one259 Example 259a{2-[1-Methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-6-{6-oxo-8-thia-5azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}phenyl}methylAcetate 259a

A 25 mL sealed tube was charged with(2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methylacetate 111a (571 mg, 1.2 mmol),5-bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one146a (400 mg, 1.2 mmol), CH₃COONa (195 mg, 2.4 mmol), K₃PO₄ (631 mg, 2.4mmol), PdCl₂(dppf) (97 mg, 0.12 mmol) suspended in CH₃CN (25 mL) and H₂O(1 mL). The mixture was heated at 110° C. for 2 hours. It was thenevaporated and the residue was purified by column chromatography elutingwith 20:1 methylene chloride/methanol to give 259a as a brown solid (500mg, 69%). MS: (M+H)⁺ 613.

A solution of 259a (500 mg, 0.82 mmol) in propan-2-ol (10 mL),tetrahydrofuran (10 mL) and water (2 mL) was added LiOH (1.96 g, 82mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by prep-HPLC to afford 259 as a yellowsolid (159 mg, 34%). MS: (M+H)⁺ 571. ¹H NMR (500 MHz, DMSO) δ 1.79 (s,4H), 2.35 (s, 2H), 2.53-2.55 (m, 1H), 2.76-2.79 (m, 4H), 2.84-2.88 (m,1H), 2.96-2.98 (m, 1H), 3.48 (s, 2H), 3.57 (s, 3H), 3.87-3.93 (m, 3H),3.99-4.03 (m, 1H), 4.35 (s, 2H), 4.81 (s, 1H), 5.88 (s, 1H), 7.23-7.24(d, 2H), 7.29-7.34 (m, 2H), 7.43-7.46 (d, 1H), 7.97-7.98 (d, 1H), 8.10(s, 1H).

Example 26010-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one260 Example 260a10-[5-Fluoro-2-(acetoxymethyl)-3-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one260a

To a microwave tube equipped with a stirring bar,5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one130c (162 mg, 0.429 mmol), boronic ester 212b (347 mg, 0.700 mmol),Pd(PPh₃)₄ (24.8 mg, 0.022 mmol), Na₂CO₃ aqueous solution (1.0 N, 1.42mL, 1.42 mmol), 1,2-dimethoxyethane (4.0 mL) were added. The mixture wasreacted in microwave at 130° C. for 15 min. Dichloromethane (200 mL) wasadded and the resulting mixture was washed with water (3×30 mL), brine(30 mL×1), dried over MgSO₄, filtered, and removed solvent in vacuo.Silica gel column chromatography (methanol:dichloromethane=5:95) gave260a.

To a round-bottomed flask equipped with a stirring bar, 260a, THF (5mL), i-PrOH (5 mL), H₂O (5 mL), LiOH H₂O (300 mg) were added. Theresulting mixture was stirred at RT for 1 hr. Removed all the solvent invacuo and the resulting residue was added to dichloromethane (200 mL),the solution was washed with water (3×30 mL), brine (30 mL), dried overMgSO₄, filtered, and removed solvent in vacuo. Silica gel columnchromatography (MeOH:dichloromethane=10:90) gave alcohol 260 as yellowsolids, 48 mg. MS (ESI+) m/z 625.5 (M+H).

Example 26110-[5-Fluoro-2-(hydroxymethyl)-3-{1-methyl-5-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one261 Example 261a10-[5-Fluoro-2-(acetoxymethyl)-3-{1-methyl-5-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one261a

In a 10-mL microwave reaction vessel equipped with a magnetic stirringbar were placed5-bromo-1-methyl-3-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one205b (150 mg, 0.43 mmol),10-[2-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one230a (248 mg, 0.50 mmol), Pd(PPh₃)₄ (30 mg, 0.026 mmol) in 2 N Na₂CO₃ (2mL) and 1,2-dimethoxyethane (2 mL). After the reaction mixture wasstirred at 125° C. for 10 minutes, it was purified by flashchromatography (dichloromethane:methanol, 3:1) to give 36% (100 mg) of261a as a solid.

A 25-mL, single-necked, round-bottomed flask equipped with a magneticstirring bar was charged with 261a (100 mg, 0.16 mmol), LiOH.H₂O (200mg, 4.8 mmol), THF (2 mL), isopropanol (2 mL), and water (2 mL). Afterthe reaction mixture was stirred at room temperature for 2 h, it waspartitioned between dichloromethane (5 mL) and water (5 mL), and theorganic phase was extracted with dichloromethane (5 mL×3). The combinedorganic phases were washed with water (2×5 mL) and brine (5 mL), dried(Na₂SO₄), and concentrated. The crude product was re-dissolved indichloromethane (3 mL). To this solution was added hexane (10 mL) andthe resulting precipitate was filtered to give 36% yield (34 mg) of 261.MS(ESI⁺) m/z 597.5 (M+H).

Example 26210-[3-(5-{[5-(1-Ethylazetidin-3-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one262 Examples 262a and 262b

Following Example 271a, 262b was produced using 250a (305 mg, 0.84 mmol)in Step 1 and using 189a (302 mg, 0.67 mmol) in Step 2 in Example 271b.The product was purified via column chromatography: ISCO 12 g silica,0-10% MeOH, to give desired product 262b (105 mg, 19% yield).

Following Example 119, 262a (105 mg, 0.36 mmol), 1N LiOH (0.8 mL), THF(2 mL) and isopropanol (2 mL) were reacted to give 262 (85 mg, 87%yield). MS (ESI+) m/z 611.5 (M+H).

Example 2632-(5-Fluoro-2-(hydroxymethyl)-3-(5-(2-methoxypyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one263 Example 263a5-Bromo-3-(2-methoxypyrimidin-4-ylamino)-1-methylpyridin-2(1H)-one 263a

Following Example 112a, 2-methoxypyrimidin-4-amine (0.625 g, 5 mmol),3,5-dibromo-1-methyl-1H-pyridin-2-one (1.34 g, 5 mmol), cesium carbonate(4.88 g, 15 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.465 g,0.5 mmol), Xantphos (0.58 g, 1 mmol) and 1,4-dioxane (50 mL) were heatedat 100° C. for 24 hours. The mixture was cooled to room temperature, andfiltered through a pad of Celite 521. The filter cake was washed with9:1 methylene chloride/methanol (2×25 mL), and the combined filtrateswere concentrated to dryness. The residue was dissolve in methylenechloride, diethyl ethyl was added, and the resulting precipitate wasfiltered to give a quantitative yield (1.57 g) of 263a as a green solid:MS (ESI+) m/z 313.1 (M+H).

Example 263b4-Fluoro-2-(5-(2-methoxypyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 263b

Following Example 121b, 263a (158 mg, 0.5 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (242 mg, 0.5 mmol), 1M sodium carbonate solution (2 mL, 2mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and1,2-dimethoxyethane (5 mL) were heated at 130° C. for 15 minutes in themicrowave reactor. Work-up and flash column chromatography (silica,60:35:5 methylene chloride/diethyl ether/methanol) gave a 98% yield (290mg) of 263b as yellow oil: MS (ESI+) m/z 587.6 (M+H).

Following Example 121, a mixture of THF (2 mL), water (1 mL) andisopropanol (2 mL), 263b (290 mg, 0.5 mmol) and lithium hydroxidemonohydrate (105 mg, 2.5 mmol) were reacted. Work-up and flash columnchromatography (NH-silica, ethyl acetate/hexanes) gave a 26% yield (70mg) of 263 as a solid: MS (ESI+) m/z 545.1 (M+H).

Example 26410-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-[1-(oxetan-3-yl)piperidin-4-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one264 Example 264a tert-Butyl4-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)piperidine-1-carboxylate264a

Following Example 112a, tert-butyl4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (1.9 g, 5.5 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (1.47 g, 5.5 mmol), cesiumcarbonate (5.36 g, 16.5 mmol), tris(dibenzylideneacetone)dipalladium(0)(0.53 g, 0.55 mmol), Xantphos (0.63 g, 1.1 mmol) and 1,4-dioxane (50 mL)were heated at 100° C. for 8 hours. Work-up and concentrated to dryness.Wash the resulting solid with diethyl ether, filtered and give 56% yield(1.4 g) of 264a as a grey solid: MS (ESI+) m/z 465.2 (M+H).

Example 264b5-Bromo-1-methyl-3-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one264b

Following Example 121c, 264a (0.58 g, 1.25 mmol), trifluoroacetic acid(0.96 mL, 12.5 mmol) and methylene chloride (20 mL) were reacted.Work-up and concentrated to afford a quantitative yield of 264b (454 mg)as yellow oil, which was used without purification in the next step. MS(ESI+) m/z 365.2 (M+H).

Example 264c5-Bromo-1-methyl-3-(5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one264c

Following Example 214b, 264b (450 mg, 1.25 mmol), oxetan-3-one (800 mg,11.1 mmol) in methanol (10 mL) were mixed. Sodium cyanoborohydride (236mg, 3.75 mmol) and zinc chloride (256 mg, 1.88 mmol) in methanol (10 mL)was added, and the reaction was heated at 48° C. for 12 hours. Work-upand flash column chromatography (silica, 60:35:5 methylenechloride/diethyl ether/methanol) afford a 30% yield (160 mg) of 264c asa light green solid: MS (ESI+) m/z 421.1 (M+H).

Following Example 121b, 264c (160 mg, 0.38 mmol), 230a (188 mg, 0.38mmol), 1M sodium carbonate solution (1.5 mL, 1.5 mmol),tetrakis(triphenylphosphine)-palladium(0) (22 mg, 0.019 mmol) and1,2-dimethoxyethane (3.5 mL) were heated at 130° C. for 15 minutes inthe microwave reactor. Work-up and flash column chromatography (silica,9:1 methylene chloride/methanol) gave a mixture (110 mg) of compound264c and 264 as yellow oil. The mixture (110 mg) was deprotected usingthe same procedure as for 121, except using a mixture of THF (1 mL),water (0.5 mL) and isopropanol (1 mL), and lithium hydroxide monohydrate(50 mg, 1.2 mmol). Work-up and flash column chromatography (NH-silica,ethyl acetate/hexanes) give a 56% yield (60 mg) of compound 264 as ayellow solid: MS (ESI+) m/z 667.6 (M+H).

Example 2652-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one265 Example 265a4-Fluoro-2-(1-methyl-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 265a

Following Example 121b, 264c (210 mg, 0.5 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (242 mg, 0.5 mmol), 1M sodium carbonate solution (2 mL, 2mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and1,2-dimethoxyethane (5 mL) were heated at 130° C. for 15 minutes in themicrowave reactor. Work-up and flash column chromatography (silica, 9:1methylene chloride/methanol) gave a 69% yield (240 mg) of 265a as brownoil: MS (ESI+) m/z 695.5 (M+H).

Following Example 121, a mixture of THF (2 mL), water (1 mL) andisopropanol (2 mL), 265a (240 mg, 0.35 mmol) and lithium hydroxidemonohydrate (100 mg, 2.5 mmol) were reacted. Work-up and flash columnchromatography (NH-silica, ethyl acetate/hexanes) give a 30% yield (70mg) of 265 as a yellow solid: MS (ESI+) m/z 653.6 (M+H).

Example 26610-[5-Fluoro-2-(hydroxymethyl)-3-{4-methyl-6-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one266 Example 266a5-Bromo-1-methyl-3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyridin-2(1H)-one266a

A 100 mL round bottom flask with a magnetic stirrer was charged with258b (350 mg, 0.8 mmol), formaldehyde (37% aqueous soln, 4.1 mmol),NaBH₃CN (150 mg, 2.4 mmol),

ZnCl₂ (170 mg, 1.2 mmol) in methanol (46 mL). The mixture was stirredfor 16 h at room temperature. After this time, the mixture wasconcentrated under reduced pressure and 10% aqueous K₂CO₃ (25 mL). Thedesired product crashed out of this mixture and was filtered. Uponwashing with diethyl ether (20 mL) afforded a 85% yield (240 mg) of266a.

Example 266b10-[5-Fluoro-2-(acetoxymethyl)-3-{4-methyl-6-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one266b

A microwave tube equipped with a magnetic stirrer was charged with 266a(240 mg, 0.7 mmol), 210d (460 mg, 0.9 mmol), 1,2-dimethoxyethane (8 mL)and 1M aqueous sodium carbonate (2 mL). After bubbling N₂ for 15 min,Pd(PPh₃)₄ (40 mg, 0.03 mmol) was added. The mixture was heated inmicrowave to 120° C. for 10 min. After this time, ethyl acetate (5 mL)and water (5 mL) were added. The separated aqueous layer was extractedwith ethyl acetate (2×5 mL). The combined organics were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography eluting with a gradient of methylene chloride—9:1methylene chloride:methanol to afford a 27% yield (120 mg) of 266b.

A 25 mL round bottom flask with a magnetic stirrer was charged with 266b(120 mg, 0.2 mmol), lithium hydroxide (40 mg, 0.9 mmol), THF (1 mL),isopropanol (1 mL) and water (2 mL). The mixture stirred at rt for 30min. After this time, ethyl acetate (5 mL) and water (5 mL) were added.The separated aqueous layer was extracted with ethyl acetate (2×5 mL).The combined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography using the Biotage KPNH12+M column eluting with a gradient of hexanes—ethyl acetate to afford a45% yield (50 mg) of 266. MS (ESI+) m/z 597.4 (M+H).

Example 2675-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one267 Example 267a[4-Fluoro-2-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 267a

A sealed tube was charged with the mixture of5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one130c (400 mg, 1.0 mmol),(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b (534 mg, 1.0 mmol), Pd(dppf)Cl₂ (87 mg, 0.1 mmol),K₃PO₄.3H₂O (569 mg, 2.0 mmol), and NaOAc (175 mg, 2.0 mmol) in CH₃CN (20mL). The system was evacuated and then refilled with N₂. And thereaction mixture was heated at 110° C. for 2 h. Then, the mixture wascooled to room temperature and filtered. The filtrate was concentratedunder reduced pressure and the resulting residue was purified by columnchromatography eluting with 10:1 methylene chloride/methanol to give267a as a brown solid (350 mg, 49%). MS: [M+H]⁺ 670.

A solution of 267a (100 mg, 0.15 mmol) in propan-2-ol (5 mL),tetrahydrofuran (5 mL) and water (1 mL) was added LiOH (358 mg, 15mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by prep-HPLC to afford 267 as a yellowsolid (18 mg, 19%). MS: (M+H)⁺ 628. ¹H NMR (500 MHz, MEOD) δ 1.83-1.96(m, 8H), 2.53-2.66 (m, 8H), 2.85 (t, 2H), 2.92-2.97 (m, 1H), 3.04-3.07(m, 1H), 3.23-3.26 (d, 2H), 3.98-4.01 (m, 1H), 4.12-4.15 (m, 1H),4.48-4.55 (m, 2H), 7.05 (d, 1H), 7.20-7.23 (m, 2H), 7.39 (d, 1H),7.55-7.57 (m, 1H), 8.12 (s, 1H), 8.65 (s, 1H).

Example 2685-{3-[5-({5-[2-(Dimethylamino)ethoxy]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-5-fluoro-2-(hydroxymethyl)phenyl}-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one268 Example 268a N,N-Dimethyl-2-(6-nitropyridin-3-yloxy)ethanamine 268a

A mixture of 6-nitropyridin-3-ol (0.5 g, 3.57 mmol),2-chloro-N,N-dimethylethanamine hydrochloride (0.61 g, 4.29 mmol) andCs₂CO₃ (2.56 g, 7.85 mmol) in DMF (7 mL) was stirred at 120° C. in asealed tube for 15 hr. The mixture was filtered and the filtrate wasworked up with ethyl acetate and water. The aqueous phase was extractedwith ethyl acetate. The combined extracts were dried over sodium sulfateand concentrated under reduced pressure. The residue was purified onflash column to give 268a (0.46 g, 61%). MS: [M+H]⁺ 212.

Example 268b 5-(2-(Dimethylamino)ethoxy)pyridin-2-amine 268b

A 100-mL Parr hydrogenation bottle was purged with nitrogen and chargedwith 268a (0.92 g, 4.36 mmol), 10% palladium on carbon (50% wet, 0.2 g)and methanol (30 mL). The bottle was evacuated, charged with hydrogengas to a pressure of 25 psi and shaken for 2 h on a Parr hydrogenationapparatus. The hydrogen was then evacuated and nitrogen charged to thebottle. The catalyst was removed by filtration through a pad of Celiteand the filtrate was concentrated under reduced pressure to afford 268b(0.66 g, 83%). MS: [M+H]⁺ 182.

Example 268c5-Bromo-3-(5-(2-(dimethylamino)ethoxy)pyridin-2-ylamino)-1-methy-1pyridin-2(1H)-one268c

A mixture of 268b (570 mg, 3.15 mmol), XantPhos (109 mg, 0.19 mmol),Pd₂dba₃ (230 mg, 0.25 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (918mg, 3.46 mmol) and Cs₂CO₃ (2.05 g. 6.3 mmol) in 1,4-dioxane (20 mL) washeated at reflux for 2 h. After the completion of the reaction, themixture was filtered off and washed with methanol (100 mL). The filtratewas evaporated in vacuo. The residue was purified on reverse phaseCombi-flash to give 268c (922 mg, 80%). MS: [M+H]⁺ 367.

Example 268d{2-[5-({5-[2-(Dimethylamino)ethoxy]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl}methylAcetate 268d

A mixture of 268c (360 mg, 0.99 mmol),(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 212b (494 mg, 0.99 mmol), PdCl₂(dppf) (86 mg, 0.12 mmol), K₃PO₄(150 mg), and NaOAc (50 mg) in MeCN (6 mL) and water (2 mL) was heatedat 110° C. in a sealed tube for 2 h. The solvent was evaporated invacuo. The residue was purified on reverse phase Combi-flash to give268d (367 mg, 60%). MS: [M+H]⁺ 660.

A mixture of 268d (700 mg, 1.06 mmol) and LiOH hydrate (446 mg, 10.6mmol) in isopropanol (15 mL) and water (5 mL) was stirred at 30° C. for2 h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (2×20 mL). The combined extracts were concentratedunder reduced pressure. The residue was purified on prep-HPLC to give268 (94 mg, 14%). MS: [M+H]⁺ 618. ¹H NMR (500 MHz, CDCl3) δ 8.54 (d,J=2.0, 1H), 7.95 (d, J=3.0, 1H), 7.80 (s, 1H), 7.48 (d, J=2.5, 1H),7.23-7.21 (m, 1H), 7.16-7.14 (m, 1H), 6.98-6.96 (m, 1H), 6.81 (d, J=9.0,1H), 4.57 (d, J=11.5, 1H), 4.30 (t, J=10.5, 1H), 4.20-4.02 (m, 4H),3.87-3.80 (m, 1H), 3.69 (s, 3H), 3.00-2.84 (m, 4H), 2.75-2.73 (m, 2H),2.59-2.48 (m, 2H), 2.37 (s, 6H), 1.94-1.83 (m, 4H).

Example 2695-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one269 Example 269a5-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one269a

To a microwave tube equipped with a stirring bar,5-bromo-3-(5-(4-ethyl-piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one138c (300 mg, 0.765 mmol), boronic ester 212b (420.1 mg, 0.841 mmol),Pd(PPh₃)₄ (44.2 mg, 0.038 mmol), Na₂CO₃ aqueous solution (1.0 N, 2.52mL, 2.52 mmol), 1,2-dimethoxyethane (4.0 mL) were added. The mixture wasreacted in microwave at 130° C. for 15 min. Methylene chloride (200 mL)was added and the resulting mixture was washed with water (3×30 mL),brine (30 mL), dried over MgSO₄, filtered, and removed solvent in vacuo.Silica gel column chromatography (methanol:methylene chloride=5:95) gaveacetate 269a.

To a round-bottomed flask equipped with a stirring bar, 269a, THF (5mL), isopropanol (5 mL), water (5 mL), LiOH H₂O (300 mg) were added. Theresulting mixture was stirred at RT for 1 hr. The solvent was removed invacuo and the resulting residue was added to methylene chloride (200mL), the solution was washed with water (3×30 mL), brine (30 mL), driedover MgSO₄, filtered, and removed solvent in vacuo. Silica gel columnchromatography (methanol:methylene chloride=10:90) gave 269 as a lightbrown solid, 158 mg. MS (ESI+) m/z 643.4 (M+H).

Example 2703-(5-((2-(Dimethylamino)ethyl)(methyl)amino)pyridin-2-ylamino)-5-(5-fluoro-2-(hydroxymethyl)-3-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta-[4,5]thieno[2,3-c]pyridine-1(2H)-yl)phenyl)-1-methylpyridin-2(1H)-one270 Example 270aN¹,N¹,N²-Trimethyl-N²-(6-nitropyridin-3-yl)ethane-1,2-diamine 270a

A 100-mL round-bottomed flask equipped with a magnetic stirrer wascharged with 1e (3.00 g, 14.8 mmol),N¹,N¹,N²-trimethylethane-1,2-diamine (2.26 g, 22.2 mmol) andN,N-dimethylacetamide (10 mL). N,N-di-isopropylethylamine (3.69 g, 28.6mmol) and tetrabutylammonium iodide (8.18 g, 22.8 mmol) were added, andthe reaction mixture was stirred at 90° C. for 14 h. After this time,the reaction was cooled to room temperature and poured into water (20mL). The resulting mixture was extracted with ethyl acetate (100 mL).The organic layer was separated and dried over sodium sulfate. Thedrying agent was removed by filtration, and the filtrate wasconcentrated under reduced pressure. Purification of the resultingresidue by column chromatography afforded 270a in 75% yield (2.50 g) asa yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, 1H, J=9.1 Hz), 7.98 (d,1H, J=3.2 Hz), 7.00 (dd, 1H, J=9.1, 3.2 Hz), 3.58 (t, 1H, J=6.9 Hz),3.14 (s, 3H), 2.52 (t, 2H, J=7.1 Hz), 2.29 (s, 6H); MS (ESI+) m/z 225.1(M+H).

Example 270b N⁵-(2-(Dimethylamino)ethyl)-N⁵-methylpyridine-2,5-diamine270b

A 250-mL Parr reactor bottle was purged with nitrogen and charged with10% palladium on carbon (50% wet, 1.00 g dry weight) and a solution of270a (2.20 g, 9.80 mmol) in ethanol (150 mL). The bottle was attached toa Parr hydrogenator, evacuated, charged with hydrogen gas to a pressureof 50 psi and shaken for 3 h. After this time, the hydrogen wasevacuated, and nitrogen was charged into the bottle. Celite 521 (1.00 g)was added, and the mixture was filtered through a pad of Celite 521. Thefilter cake was washed with ethanol (2×25 mL), and the combinedfiltrates were concentrated to dryness under reduced pressure to afforda quantitative yield of 270b (1.91 g) as a purple oil: ¹H NMR (500 MHz,CDCl₃) δ 7.67 (d, 1H, J=2.9 Hz), 7.05 (dd, 1H, J=8.5, 2.9 Hz), 6.48 (dd,1H, J=8.9, 0.5 Hz), 4.04 (br s, 2H), 3.28 (t, 2H, J=7.1 Hz), 2.84 (s,3H), 2.43 (t, 2H, J=7.4 Hz), 2.26 (s, 6H); MS (ESI+) m/z 195.2 (M+H).

Example 270c5-Bromo-3-(5-((2-(dimethylamino)ethyl)(methyl)amino)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one270c

A 100-mL two-neck round-bottomed flask equipped with a reflux condenser,magnetic stirrer and nitrogen inlet was charged with 270b (1.00 g, 5.20mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.53 g, 5.72 mmol), cesiumcarbonate (5.09 g, 15.6 mmol), and 1,4-dioxane (52 mL). After bubblingnitrogen through the resulting suspension for 30 min, Xantphos (257 mg,0.442 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (239 mg, 0.260mmol) were added, and the reaction mixture was heated at reflux for 3 h.After this time, the mixture was cooled to room temperature and dilutedwith ethyl acetate (150 mL) and water (30 mL). The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate (3×150mL). The combined organic layers were dried over sodium sulfate andconcentrated under reduced pressure. The residue was triturated withmethanol (20 mL) to afford a 63% yield (700 mg) of 270c as an off-whitesolid: mp 161-163° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (d, 1H, J=2.3Hz), 8.39 (s, 1H), 7.75 (d, 1H, J=2.4 Hz), 7.40 (d, 1H, J=2.4 Hz), 7.17(m, 2H), 3.50 (s, 3H), 3.56 (t, 2H, J=6.9 Hz), 2.86 (s, 3H), 2.35 (t,2H, J=7.1 Hz), 2.16 (s, 6H); MS (ESI+) m/z 380.1 (M+H).

Example 270d3-(5-((2-(Dimethylamino)ethyl)(methyl)amino)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one270d

A 100-mL single-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 270c(500 mg, 1.32 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (668 mg, 2.63mmol), potassium acetate (389 mg, 3.96 mmol), and 1,4-dioxane (10 mL).After bubbling nitrogen through the resulting suspension for 30 min,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (97 mg,0.132 mmol) was added, and the reaction mixture was heated at reflux for1 h. After this time, the mixture was cooled to room temperature anddiluted with ethyl acetate (150 mL) and water (30 mL). The organic layerwas separated, and the aqueous layer was extracted with ethyl acetate(3×150 mL). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure to afford 270d in a crudequantitative yield. The residue was used without further purification.

A 50-mL three-neck round-bottomed flask equipped with a refluxcondenser, magnetic stirrer and nitrogen inlet was charged with 247a(420 mg, 0.901 mmol), 270d (290 mg, 0.690 mmol), sodium carbonate (220mg, 2.07 mmol), water (2 mL) and 1,4-dioxane (8 mL). After bubblingnitrogen through the resulting suspension for 30 min,tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) was added,and the reaction mixture was heated at reflux for 2 h. After this time,the mixture was cooled to room temperature and diluted with ethylacetate (150 mL) and water (30 mL). The organic layer was separated, andthe aqueous layer was extracted with ethyl acetate (3×150 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The residue was dissolved in a mixture of THF(10 mL), methanol (10 mL) and water (10 mL). Lithium hydroxidemonohydrate (420 mg, 10.0 mmol) was added to the resulting solution. Themixture was stirred for 2 h at room temperature and then concentrated invacuo. The residue was partitioned between ethyl acetate (150 mL) andwater (30 mL). The organic layer was separated, and the aqueous layerwas extracted with a 20% (v/v) solution of methanol in methylenechloride (3×150 mL). The combined organic layers were dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica, 0% to 20% methanol/methylenechloride) to afford a 14% yield (53 mg) of 270 as an off-white solid: mp106-107° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (d, 1H, J=2.5 Hz), 8.20(s, 1H), 7.69 (d, 1H, J=2.5 Hz), 7.32 (m, 2H), 7.17 (m, 3H), 4.84 (t,1H, J=4.0 Hz), 4.33 (m, 2H), 4.04 (m, 1H), 3.84 (m, 1H), 3.58 (s, 3H),3.03 (m, 1H), 2.89 (m, 1H), 2.75 (s, 2H), 2.53 (d, 2H, J=8.9 Hz), 2.32(t, 2H, J=7.2 Hz), 2.14 (s, 6H), 1.23 (s, 6H); MS (ESI+) m/z 645.3(M+H).

Example 27110-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylazetidin-3-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one271 Example 271a10-[5-Fluoro-2-(acetoxymethyl)-3-(1-methyl-5-{[5-(1-methylazetidin-3-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one271a

A microwave tube equipped with a magnetic stirrer was charged with5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridin-2(1H)-one(172a) (216 mg, 0.6 mmol), 230a (390 mg, 0.8 mmol), 1,2-dimethoxyethane(8 mL) and 1M aqueous sodium carbonate (2 mL). After bubbling N₂ for 15min, Pd(PPh₃)₄ (36 mg, 0.03 mmol) was added. The mixture was heated inmicrowave to 130° C. for 15 min. After this time, ethyl acetate (5 mL)and water (5 mL) were added. The separated aqueous layer was extractedwith ethyl acetate (2×5 mL). The combined organics were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography eluting with a gradient of methylene chloride—9:1methylene chloride:methanol to afford a 30% yield (120 mg) of 271a.

A 25 mL round bottom flask with a magnetic stirrer was charged with 271a(110 mg, 0.2 mmol), lithium hydroxide (40 mg, 0.9 mmol), THF (1 mL),isopropanol (1 mL) and water (2 mL). The mixture stirred at rt for 30min. After this time, ethyl acetate (5 mL) and water (5 mL) were added.The separated aqueous layer was extracted with ethyl acetate (2×5 mL).The combined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography using the Biotage KPNH12+M column eluting with a gradient of hexanes—ethyl acetate to affordan 88% yield (94 mg) of 271. MS (ESI+) m/z 597.4 (M+H).

Example 27210-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one272 Example 272a10-[3-(5-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(acetoxymethyl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one272a

To a microwave tube equipped with a stirring bar, 182b (270 mg, 0.579mmol),3-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one201a (382 mg, 0.868 mmol), Pd(PPh₃)₄(34 mg, 0.029 mmol), Na₂CO₃ aqueoussolution (1.0 N, 1.91 mL, 1.91 mmol), 1,2-dimethoxyethane (4.0 mL) wereadded. The mixture was reacted in microwave at 130° C. for 15 min.Methylene chloride (200 mL) was added and the resulting mixture waswashed with water (30 mL×3), brine (30 mL×1), dried over MgSO₄,filtered, and removed solvent in vacuo. Silica gel column chromatography(methanol:methylene chloride=5:95) gave 272a.

To a round-bottomed flask equipped with a stirring bar, 272a, THF (5mL), isopropanol (5 mL), water (5 mL), LiOH H₂O (300 mg) were added. Theresulting mixture was stirred at RT for 1 hr. The solvent was removed invacuo and the resulting residue was added to methylene chloride (200mL), the solution was washed with water (30 mL×3), brine (30 mL×1),dried over MgSO₄, filtered, and removed solvent in vacuo. Silica gelcolumn chromatography (methanol:methylene chloride=10:90) gave 272 asyellow solids, 143 mg. MS (ESI+) m/z 657.6 (M+H).

Example 27310-{5-Fluoro-3-[5-({5-[4-(2-fluoroethyl)piperazin-1-yl]pyridine-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-2-(hydroxymethyl)phenyl}-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one273 Example 273b10-{5-Fluoro-3-[5-({5-[4-(2-fluoroethyl)piperazin-1-yl]pyridine-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-2-(acetoxymethyl)phenyl}-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one273b

Following Example 186f, 273a (which was prepared in situ from 217d usingconditions analogous to those used to prepare 270d) (200 mg, 0.49 mmol)and 189a (176 mg, 0.39 mmol) were reacted to give 273b (115 mg, 33%yield).

Following Example 186, 273b (115 mg, 0.16 mmol), 1N LiOH (0.82 mL), THF(3 mL) and isopropanol (3 mL) were reacted and purified via HPLC(acetonitrile/water/TFA). To the residue was added ethyl acetate andsaturated aqueous sodium bicarbonate and the mixture stirred for ˜15min. The layers were separated and the organics were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum to give 273 (23 mg, 22% yield). MS (ESI+) m/z 658.5 (M+H).

Example 27410-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(morpholin-4-ylmethyl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one274 Example 274a5-Bromo-1-methyl-3-(5-(morpholinomethyl)pyridin-2-ylamino)pyridin-2(1H)-one274a

Following Example 186d, compound 274a was prepared.

Example 274c10-[5-Fluoro-2-(acetoxymethyl)-3-(1-methyl-5-{[5-(morpholin-4-ylmethyl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one274c

Following Examples 186e and 186f, 274a (300 mg, 0.79 mmol) in Step 1 toafford 274b in situ and then reacting with 189a (284 mg, 0.63 mmol) inStep 2 gave 274c (250 mg, 46% yield).

Following Example 119, 274c (250 mg, 0.36 mmol), 1N LiOH (1.5 mL), THF(3 mL) and isopropanol (3 mL) were reacted, purified via columnchromatography: ISCO 12 g silica, 0-10% methanol, then triturated withmethylene chloride/diethylether to give 274 (89 mg, 39% yield). MS(ESI+) m/z 627.5 (M+H).

Example 2752-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one275

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 197e (210 mg, 0.560 mmol),118f (330 mg, 0.710 mmol), sodium carbonate (175 mg, 1.70 mmol), water(2 mL) and 1,4-dioxane (8 mL). After bubbling nitrogen through theresulting suspension for 30 min,tetrakis(triphenyl-phosphine)palladium(0) (64 mg, 0.055 mmol) was added.A reflux condenser was attached to the flask, and the reaction mixturewas heated at 100° C. for 2 h. After this time, the mixture was dilutedwith 90:10 methylene chloride/methanol (100 mL) and water (75 mL), andthe layers were separated. The aqueous layer was extracted with 90:10methylene chloride/methanol (2×50 mL), and the combined organic extractswere washed with brine (100 mL) and dried over sodium sulfate. Thedrying agent was removed by filtration. The filtrate was concentratedunder reduced pressure, and the resulting residue was dissolved in amixture of THF (3 mL), water (3 mL) and methanol (3 mL). Lithiumhydroxide monohydrate (100 mg, 2.40 mmol) was added, and the reactionwas stirred at room temperature for 2 h. After this time, the mixturewas diluted with 90:10 methylene chloride/methanol (100 mL) and water(50 mL), and the layers were separated. The aqueous layer was extractedwith 90:10 methylene chloride/methanol (2×75 mL), and the combinedorganic extracts were dried over sodium sulfate. The drying agent wasremoved by filtration. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by flash columnchromatography (silica, 0% to 10% methanol/methylene chloride) to afford275 in 8% yield (35 mg) as an amorphous off-white solid: mp 180-181° C.;¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (d, 1H, J=2.5 Hz), 8.31 (s, 1H), 7.84(d, 1H, J=2.5 Hz), 7.42 (t, 1H, J=8.0 Hz), 7.35 (m, 1H), 7.26 (d, 2H,J=8.0 Hz), 7.19 (d, 1H, J=9.0 Hz), 6.00 (s, 1H), 4.69 (t, 1H, J=5.0 Hz),4.31 (d, 2H, J=4.5 Hz), 3.99 (m, 1H), 3.95 (m, 1H), 3.88 (m, 2H), 3.57(s, 3H), 3.05 (m, 5H), 2.90 (m, 1H), 2.70 (t, 2H, J=6.0 Hz), 2.42 (m,5H), 2.19 (s, 3H), 1.91 (m, 2H), 2.73 (m, 2H); MS (ESI+) m/z 594.3(M+H).

Example 27610-[5-Fluoro-2-(hydroxymethyl)-3-{1-methyl-5-[(5-methyl-1H-pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one276 Example 276a10-[5-Fluoro-2-(hydroxymethyl)-3-{1-methyl-5-[(5-methyl-1H-pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one276a

A microwave tube equipped with a magnetic stirrer was charged with5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 112a(150 mg, 0.5 mmol), 230a (350 mg, 0.7 mmol), 1,2-dimethoxyethane (6.4mL) and 1M aqueous sodium carbonate (1.6 mL). After bubbling N₂ for 15min, Pd(PPh₃)₄ (31 mg, 0.03 mmol) was added. The mixture was heated inmicrowave to 130° C. for 15 min. After this time, ethyl acetate (5 mL)and water (5 mL) were added. The separated aqueous layer was extractedwith ethyl acetate (2×5 mL). The combined organics were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography eluting with a gradient of methylene chloride—60:35:5methylene chloride:diethyl ether:methanol to afford a 16% yield (50 mg)of 276a.

A 25 mL round bottom flask with a magnetic stirrer was charged with 276a(50 mg, 0.1 mmol), lithium hydroxide (18 mg, 0.4 mmol), THF (0.4 mL),isopropanol (0.4 mL) and water (1 mL). The mixture stirred at rt for 30min. After this time, ethyl acetate (5 mL) and water (5 mL) were added.The separated aqueous layer was extracted with ethyl acetate (2×5 mL).The combined organics were washed with brine (10 mL), dried over sodiumsulfate and filtered. The mixture was concentrated under reducedpressure to near dryness when the desired product crashed out and wasfiltered. Upon washing with diethyl ether (10 mL) afforded an 87% yield(40 mg) of 276. MS (ESI+) m/z 531.4 (M+H).

Example 2775-[5-Fluoro-2-(hydroxymethyl)-3-{1-methyl-5-[(5-{[methyl(propan-2-yl)amino]methyl}pyridine-2-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one277 Example 277a5-[5-Fluoro-2-(acetoxymethyl)-3-{1-methyl-5-[(5-{[methyl(propan-2-yl)amino]methyl}pyridine-2-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one277a

Following Example 186, 186e (270 mg, 0.74 mmol) produced in situ wasreacted with 212a (267 mg, 0.59 mmol) in Step 2. Purified by columnchromatography: ISCO 12 g silica, 50-100% ethyl acetate/hexanes then0-15% MeOH/CH2Cl2 to give 277a (270 mg, 55% yield).

Following Example 119, 277a (270 mg, 0.41 mmol), 1N LiOH (2.0 mL), THF(4 mL) and isopropanol (4 mL) were reacted, and triturated with ether togive 277 (185 mg, 73% yield). MS (ESI+) m/z 616.4 (M+H).

Example 27810-[5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one278 Example 278a10-[5-Fluoro)-3-(4-methyl-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)benzylacetate]-4,4-dimethyl-7-thia-10-azatricyclo-[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one278a

Following Example 136d, 282c and(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b were reacted to give 278a in 62% yield. LCMS: (M+H)⁺ 684

Following Example 136, 278a was converted to 278 in 39% yield. LCMS:(M+H)⁺ 642. ¹H NMR (500 MHz, DMSO) δ 9.22 (s, 1H), 7.90 (s, 1H), 7.87(s, 1H), 7.48 (s, 1H), 7.36 (dd, J=9.5, 1H), 7.31 (dd, J=9, 1H), 7.16(s, 1H), 7.14 (s, 1H), 4.46 (m, 2H), 4.05 (m, 2H), 3.85 (m, 2H), 3.54(s, 3H), 3.01 (m, 1H), 2.92 (m, 3H), 2.75 (s, 2H), 2.53 (m, 2H), 2.44(m, 1H), 2.27 (s, 3H), 2.13 (m, 2H), 1.70 (m, 4H), 1.22 (s, 6H).

Example 27910-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one279 Example 279a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-[1-methyl-5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl)methylAcetate 279a

A 25 mL sealed tube was charged with5-bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one146a (340 mg, 1.0 mmol),(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b (480 mg, 1.0 mmol), CH₃COONa (168 mg, 2.0 mmol), K₃PO₄ (546mg, 2.0 mmol), PdCl₂(dppf) (84 mg, 0.1 mmol) suspended in CH₃CN (25 mL)and water (1 mL). The mixture was heated at 110° C. for 2 hours,evaporated, and the residue was purified by column chromatographyeluting with 15:1 methylene chloride/methanol to give 279a as a brownsolid (300 mg, 46%). MS: (M+H)⁺ 645.

To a solution of 279a (300 mg, 0.46 mmol) in propan-2-ol (10 mL),tetrahydrofuran (10 mL) and water (2 mL) was added LiOH (1.1 g, 57mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by prep-HPLC to afford 279 as a white solid(99 mg, 35%). MS: (M+H)⁺ 603. ¹H NMR (500 MHz, MEOD) δ 1.29 (d, 6H),2.49 (s, 3H), 2.59 (d, 2H), 2.81 (s, 2H), 2.94-2.97 (m, 3H), 3.07-3.14(m, 1H), 3.64 (s, 2H), 3.70 (s, 3H), 3.97-3.99 (m, 1H), 4.05-4.07 (t,2H), 4.12-4.15 (m, 1H), 4.47-4.54 (m, 2H), 5.89 (s, 1H), 7.19-7.22 (m,2H), 7.26 (d, 1H), 7.91 (s, 1H).

Example 28010-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one280 Example 280a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(1-methyl-5-{[6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naph-thyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl)methylAcetate 280a

A 25 mL sealed tube was charged with5-bromo-1-methyl-3-(6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one219a (400 mg, 1.0 mmol),(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b (493 mg, 1.0 mmol), CH₃COONa (168 mg, 2.0 mmol), K₃PO₄ (546mg, 2.0 mmol), PdCl₂(dppf) (84 mg, 0.1 mmol) suspended in CH₃CN (25 mL)and H₂O (1 mL). The mixture was heated at 110° C. for 2 hours. It wasthen evaporated and the residue was purified by column chromatographyeluting with 20:1 methylene chloride/methanol (20:1) to give 280a as abrown solid (400 mg, 56%). MS: (M+H)⁺ 698.

To a solution of 280a (400 mg, 0.57 mmol) in propan-2-ol (10 mL),tetrahydrofuran (10 mL) and water (2 mL) was added LiOH (1.4 g, 57mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by prep-HPLC to afford 280 as a white solid(52 mg, 14%). MS: (M+H)⁺ 656. ¹H NMR (500 MHz, MEOD) δ 1.29 (d, 6H),2.56-2.63 (q, 2H), 2.70-2.72 (t, 2H), 2.81 (s, 2H), 2.93-2.99 (m, 3H),3.08-3.12 (m, 1H), 3.47 (s, 2H), 3.72-3.74 (m, 4H), 3.96-4.01 (m, 1H),4.13-4.18 (m, 1H), 4.51-4.60 (q, 2H), 4.68-4.71 (t, 2H), 4.76-4.79 (t,2H), 6.89 (d, 1H), 7.21-7.23 (d, 2H), 7.34 (d, 1H), 7.40 (s, 1H), 8.78(s, 1H).

Example 2815-[5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one281 Example 281a[4-Fluoro-2-(4-methyl-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl]methylacetate 281a

Following Example 136d, 282c) and(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 212b were reacted to give 281a in 73% yield. LCMS: (M+H)⁺ 670

Following Example 136, 281a was converted to 281 in 70% yield. LCMS:(M+H)⁺ 628. ¹H NMR (500 MHz, DMSO) δ 9.21 (s, 1H), 7.87 (s, 1H), 7.85(s, 1H), 7.47 (s, 1H), 7.35 (dd, J=10, 1H), 7.30 (dd, J=9, 1H), 7.16 (s,1H), 7.14 (s, 1H), 4.84 (m, 1H), 4.48 (m, 1H), 4.40 (m, 1H), 3.86 (m,1H), 3.53 (s, 3H), 2.96 (m, 1H), 2.87 (m, 4H), 2.78 (m, 2H), 2.42 (m,2H), 2.19 (s, 3H), 1.96 (m, 2H), 1.80 (m, 4H), 1.62 (m, 5H).

Example 2822-(5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-(4-(1-methylpiperidin-4-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one282 Example 282a tert-Butyl4-(4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)piperidine-1-carboxylate282a

A mixture of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (2.5g, 9.06 mmol) and 3,5-dibromo-1-methylpyrazin-2(1H)-one (2.2 g, 8.23mmol) in isopropanol (30 mL) was heated at 85° C. for 15 h. After thereaction was finished, it was filtered and the solid was washed withisopropanol to afford 282a as a white solid (2.9 g, 80%). LCMS: (M+H)⁺463

Example 282b5-Bromo-1-methyl-3-(4-(piperidin-4-yl)phenylamino)pyrazin-2(1H)-one 282b

Following Example 247a, 282a was converted to 282b in 99% yield.

Example 282c5-Bromo-1-methyl-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2(1H)-one282c

Following Example 247b, 282b was converted to 282c in 65% yield.

Example 282d4-Fluoro-2-(4-methyl-6-(4-(1-methylpiperidin-4-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 282d

Following Example 247c, 282c and4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d were reacted to give 282d in 41% yield.

Following Example 136, 282d was converted to 282 in 36% yield. LCMS:(M+H)⁺ 611. ¹H NMR (500 MHz, DMSO) δ 9.22 (s, 1H), 7.90 (s, 1H), 7.88(s, 1H), 7.49 (s, 1H), 7.36 (dd, J=9.5, 1H), 7.30 (dd, J=9.5, 1H), 7.17(s, 1H), 7.15 (s, 1H), 6.54 (s, 1H), 4.47 (m, 2H), 4.15 (m, 3H), 3.88(m, 2H), 2.91 (m, 2H), 2.59 (m, 2H), 3.05 (m, 1H), 2.46 (m, 3H), 2.25(s, 3H), 2.07 (m, 2H), 1.80 (m, 2H), 1.70 (m, 6H).

Example 2832-(5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one283 Example 283a4-Fluoro-2-(4-methyl-6-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 283a

Following Example 148b, 290 mg of4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d and 209 mg5-bromo-1-methyl-3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one221b were reacted to give 283a as a yellow solid (217 mg, 58%). MS:[M+H]⁺ 699

Following Example 148, 283a was converted to 283 as a white solid (84mg, 43%). ¹H NMR (500 MHz, DMSO) δ 9.15 (s, 1H), 7.82 (s, 1H), 7.65 (d,J=8, 1H), 7.52 (s, 1H), 7.39 (dd, J=10, 1H), 7.31 (dd, J=10, 1H), 6.96(d, J=8.0, 1H), 6.53 (s, 1H), 4.87 (s, 1H), 4.49 (m, 1H), 4.42 (m, 1H),4.13 (m, 3H), 3.88 (m, 1H), 3.54 (s, 3H), 3.41 (s, 2H), 3.30 (s, 1H),2.76 (d, J=5.5, 6H), 2.58 (m, 5H), 23.2 (s, 3H), 1.79 (s, 2H), 1.70 (s,2H).

Example 28410-(3-{5-[(6-Ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-5-fluoro-2-(hydroxymethyl)phenyl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one284

In a 48-mL sealed tube equipped with a magnetic stirring bar were placed5-bromo-1-methyl-3-(6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one(143 mg, 0.4 mmol),10-[2-(acetoxymethyl)-3-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]-dodeca-2(6),7-dien-9-one230a (496 mg, 1.0 mmol), Pd(PPh₃)₄ (23 mg, 0.020 mmol) in 2 N Na₂CO₃ (4mL) and DME (4 mL). After the reaction mixture was stirred at 100° C.for 1 h, it was purified by flash chromatography(dichloromethane:methanol, 3:1) to give 7% (18 mg) of 284 MS(ESI⁺) m/z611.5 (M+H).

Example 28510-{3-[5-({5-Ethyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-5-fluoro-2-(hydroxymethyl)phenyl}-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one285 Example 285a5-Ethyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 285a

A sealed tube equipped with a magnetic stirrer was charged with1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 101c (2.8 g, 9mmol) 2M ethylamine solution in THF (27 mL). The resulting mixture washeated to 35° C. overnight. After this time, the reaction mixture wasconcentrated under reduced pressure, and to the residue was added water(50 mL) and ethyl acetate (50 mL). The aqueous layer was separated andextracted with ethyl acetate (2×50 mL). The combined organic extractswere washed with brine (100 mL) and dried over sodium sulfate. Theresulting solution was concentrated under reduced pressure to afford a100% yield (1.8 g) of crude 285a.

Example 285b 5-Ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine285b

A 500-mL Parr hydrogenation bottle was charged with 285a (1.8 g, 9mmol), 10% palladium on carbon (50% wet, 500 mg dry weight) and ethanol(100 mL). The bottle was evacuated, charged with hydrogen gas to apressure of 50 psi and shaken for 1 h on a Parr hydrogenation apparatus.The catalyst was removed by filtration through a pad of Celite 521washing with 1:1 methylene chloride:methanol (500 mL). The resultingsolution was concentrated under reduced pressure to afford a 71% yield(1.7 g) of crude 285b.

Example 285c5-Bromo-3-(5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methylpyridin-2(1H)-one285c

A sealed tube was equipped with a magnetic stirrer and charged with 285b(1.1 g, 6.4 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one 5 (1.7 g, 6.4mmol) and cesium carbonate (4.6 g, 14 mmol) in 1,4-dioxane (64 mL).After bubbling nitrogen through the solution for 30 min, Xantphos (440mg, 0.8 mmol) and tris(dibenzylideneacetone)dipalladium(0) (400 mg, 0.5mmol) were added, and the reaction mixture was heated to 100° C. for 16h. After this time, water (50 mL) and ethyl acetate (50 mL) were added.The aqueous layer was separated and extracted with ethyl acetate (2×50mL). The combined organic extracts were washed with brine (100 mL) anddried over sodium sulfate. The resulting residue was purified by columnchromatography eluting with a gradient of methylene chloride—60:35:5methylene chloride:diethyl ether:methanol to afford a 28% yield (620 mg)of 285c.

Example 285d10-{3-[5-({5-Ethyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-5-fluoro-2-(acetoxymethyl)phenyl}-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one285d

A microwave tube equipped with a magnetic stirrer was charged with 285c(190 mg, 0.5 mmol), 230a (350 mg, 0.7 mmol), 1,2-dimethoxyethane (6.4mL) and 1M aqueous sodium carbonate (1.6 mL). After bubbling N₂ for 15min, Pd(PPh₃)₄ (31 mg, 0.03 mmol) was added. The mixture was heated inmicrowave to 130° C. for 15 min. After this time, ethyl acetate (5 mL)and water (5 mL) were added. The separated aqueous layer was extractedwith ethyl acetate (2×5 mL). The combined organics were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography eluting with a gradient of methylene chloride—60:35:5methylene chloride:diethyl ether:methanol to afford a 35% yield (120 mg)of 285d.

A 25 mL round bottom flask with a magnetic stirrer was charged with 285d(120 mg, 0.2 mmol), lithium hydroxide (40 mg, 1 mmol), THF (1 mL),isopropanol (1 mL) and water (2 mL). The mixture stirred at rt for 30min. After this time, ethyl acetate (5 mL) and water (5 mL) were added.The separated aqueous layer was extracted with ethyl acetate (2×5 mL).The combined organics were washed with brine (10 mL), dried over sodiumsulfate and filtered. The mixture was concentrated under reducedpressure to near dryness when the desired product crashed out and wasfiltered. Washing with diethyl ether (10 mL) afforded an 78% yield (90mg) of 285. MS (ESI+) m/z 600.6 (M+H).

Example 2862-(3-(5-(5-((2-(Dimethylamino)ethyl)(methyl)amino)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-1(2H)-one286

Following Example 270, reaction of 212a (550 mg, 1.20 mmol) and 270d(428 mg, 1.00 mmol) afforded a 8% yield (49 mg) of 286 as an off-whitesolid: mp 122-123° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (d, 1H, J=2.0Hz), 8.20 (s, 1H), 7.69 (d, 1H, J=2.4 Hz), 7.31 (m, 2H), 7.17 (m, 3H),4.83 (t, 1H, J=4.6 Hz), 4.32 (d, 2H, J=4.3 Hz), 4.06 (m, 1H), 3.87 (m,1H), 3.58 (s, 3H), 2.96 (m, 1H), 2.86 (m, 1H), 2.83 (s, 3H), 2.78 (m,2H), 2.54 (m, 1H), 2.32 (t, 2H, J=7.0 Hz), 2.14 (s, 6H), 1.80 (m, 4H);MS (ESI+) m/z 631.3 (M+H).

Example 2875-(5-Fluoro-2-(hydroxymethyl)-3-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1(2H)-yl)phenyl)-1-methyl-3-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)pyridin-2(1H)-one287 Example 287a1-Methyl-3-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one287a

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 202a (481 mg, 1.33 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (675 mg, 2.66mmol), potassium acetate (392 mg, 3.99 mmol) and 1,4-dioxane (12 mL).After bubbling nitrogen through the resulting suspension for 30 min,Pd(dppf)Cl₂ (97.0 mg, 0.133 mmol) was added. A reflux condenser wasattached to the flask, and the reaction mixture was heated at 100° C.for 3 h. After this time, the mixture was diluted with ethyl acetate(100 mL) and water (75 mL), and the layers were separated. The aqueouslayer was extracted with ethyl acetate (2×50 mL), and the combinedorganic layers were washed with brine (100 mL) and dried over sodiumsulfate. The drying agent was removed by filtration. The filtrate wasconcentrated under reduced pressure to afford crude 287a in quantitativeyield (548 mg) as a brown semi-solid. The crude mixture was used in thenext reaction without further purification: MS (ESI+) m/z 411.2 (M+H).

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with crude 287a (274 mg, 0.668mmol, presuming quantitative yield), 247a (420 mg, 0.865 mmol), sodiumcarbonate (207 mg, 1.99 mmol), water (2 mL) and 1,4-dioxane (10 mL).After bubbling nitrogen through the resulting suspension for 30 min,tetrakis(triphenylphosphine)palladium(0) (151 mg, 0.133 mmol) was added.A reflux condenser was attached to the flask, and the reaction mixturewas heated at 90° C. for 1 h. After this time, the mixture was dilutedwith 90:10 methylene chloride/methanol (100 mL) and water (75 mL), andthe layers were separated. The aqueous layer was extracted with 90:10methylene chloride/methanol (2×50 mL), and the combined organic layerswere washed with brine (100 mL) and dried over sodium sulfate. Thedrying agent was removed by filtration. The filtrate was concentratedunder reduced pressure, and the resulting residue was dissolved in THF(5 mL), water (5 mL) and methanol (5 mL). Lithium hydroxide monohydrate(47 mg, 1.12 mmol) was added, and the mixture was stirred at roomtemperature for 2 h. After this time, the mixture was diluted with 90:10methylene chloride/methanol (100 mL) and water (50 mL), and the layerswere separated. The aqueous layer was extracted with 90:10 methylenechloride/methanol (2×75 mL), and the combined organic layers were washedwith brine (100 mL) and dried over sodium sulfate. The drying agent wasremoved by filtration. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by flash columnchromatography (silica, 80:20 methylene chloride/methanol) to afford 287in 27% yield (110 mg) as an amorphous off-white solid: mp 181-183° C.;¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (d, J=2.0 Hz, 1H), 8.49 (s, 1H), 8.07(d, J=2.5 Hz, 1H), 7.54 (dd, J=8.5, 2.5 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H),7.34 (dd, J=9.0, 2.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.19 (dd, J=9.5,2.5 Hz, 1H), 4.86 (t, J=4.0 Hz, 1H), 4.34-4.32 (m, 2H), 4.10-4.03 (m,1H), 3.87-3.83 (m, 1H), 3.59 (s, 3H), 3.25-3.20 (m, 1H), 3.05-2.99 (m,1H), 2.91-2.87 (m, 1H), 2.81-2.77 (m, 1H), 2.75 (s, 2H), 2.60-2.58 (m,2H), 2.55-2.50 (m, 2H), 2.49-2.32 (m, 1H), 2.27 (s, 3H), 2.22-2.17 (m,1H), 1.71-1.67 (m, 1H), 1.23 (s, 6H); MS (ESI+) m/z 628.3 (M+H).

Example 2882-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-1(2H)-one288

Following Example 286, reaction of 212a (450 mg, 1.04 mmol) and 287b(328 mg, 0.810 mmol) afforded a 26% yield (130 mg) of 288 as anoff-white solid: mp 164-166° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (d,1H, J=2.0 Hz), 8.55 (s, 1H), 8.06 (d, 1H, J=2.4 Hz), 7.53 (dd, 1H,J=8.5, 2.4 Hz), 7.41 (d, 1H, J=2.4 Hz), 7.32 (dd, 1H, J=9.1, 2.1 Hz),7.26 (d, 1H, J=9.0 Hz), 7.19 (dd, 1H, J=9.0, 2.0 Hz), 4.85 (t, 1H, J=4.2Hz), 4.32 (m, 2H), 4.04 (m, 1H), 3.87 (m, 1H), 3.59 (s, 3H), 3.13 (m,1H), 2.95 (m, 2H), 2.84 (m, 1H), 2.78 (m, 2H), 2.54 (m, 1H), 2.18 (q,1H, J=4.0 Hz), 2.04 (m, 4H), 1.80 (m, 6H), 1.58 (m, 1H); MS (ESI+) m/z614.3 (M+H).

Example 2892-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-morpholinopyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-1(2H)-one289 Example 289a1-Methyl-3-(5-morpholinopyridin-2-ylamino)-5-(4,4,5,5-tetra-methyl1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one289a

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and nitrogen inlet was charged with 255c (610 mg, 1.70 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (850 mg, 3.40mmol), potassium acetate (492 mg, 5.00 mmol) and 1,4-dioxane (20 mL).After bubbling nitrogen through the resulting suspension for 30 min,Pd(dppf)Cl₂/CH₂Cl₂ (122 mg, 0.200 mmol) was added. A reflux condenserwas attached to the flask, and the reaction mixture was heated at 90° C.for 2 h. After this time, the mixture was diluted with ethyl acetate(100 mL) and water (75 mL), and the layers were separated. The aqueouslayer was extracted with ethyl acetate (50 mL), and the combined organicextracts were washed with brine (50 mL) and dried over sodium sulfate.The drying agent was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by trituration with hexanes/ethyl acetate (80:20, 25 mL) toafford 289a in quantitative yield (688 mg) as a brown solid: mp 100-101°C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (d, 1H, J=1.5 Hz), 8.21 (s, 1H),7.91 (s, 1H), 7.89 (d, 1H, J=3.0 Hz), 7.66 (d, 1H, J=6.5 Hz), 7.14 (d,1H, J=9.0 Hz), 3.73 (t, 4H, J=4.5 Hz), 3.55 (s, 3H), 3.05 (t, 4H, J=4.5Hz), 1.29 (s, 12H); MS (ESI+) m/z 413.0 (M+H)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with289a (485 mg, 0.415 mmol), 247a (488 mg, 1.10 mmol), sodium carbonate(264 mg, 2.50 mmol), 1,4-dioxane (8 mL) and water (2 mL). This mixturewas degassed with nitrogen for 30 min.Tetrakis(triphenylphosphine)palladium (96 mg, 0.083 mmol) was added.After heating at 100° C. for 2 h, the reaction mixture was cooled toroom temperature and partitioned between water (40 mL) and methylenechloride (100 mL). The layers were separated, and the aqueous phase wasextracted with methylene chloride (2×50 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was dissolved in methanol (5mL), and potassium carbonate (745 mg, 5.40 mmol) was added. Afterstirring at room temperature for 1 h, the reaction mixture waspartitioned between water (20 mL) and methylene chloride (20 mL). Thelayers were separated, and the aqueous phase was extracted withmethylene chloride (2×20 mL). The organic extracts were combined, driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by flash column chromatography(silica, 0% to 15% methanol/methylene chloride) to afford 289 in 51%yield (130 mg) as a yellow solid: mp 220-221° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 8.55 (d, 1H, J=2.0 Hz), 8.37 (s, 1H), 7.87 (d, 1H, J=3.0 Hz),7.34 (m, 3H), 7.23 (d, 1H, J=9.0 Hz), 7.16 (dd, 1H, J=9.5, 3.0 Hz), 4.83(t, 1H, J=4.0 Hz), 4.32 (m, 2H), 4.05 (m, 1H), 3.86 (m, 1H), 3.71 (t,4H, J=4.5 Hz), 3.58 (s, 3H), 3.01 (t, 4H, J=4.5 Hz), 2.98 (m, 1H), 2.87(m, 1H), 2.77 (m, 2H), 2.54 (m, 1H), 1.79 (m, 4H); MS (ESI+) m/z 616.2(M+H).

Example 29010-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-[(2S)-1-methylpyrrolidin-2-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one290 Example 29110-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-[(2R)-1-methylpyrrolidin-2-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one291

Compounds 290 and 291 are enantiomers of racemate 243. The racemicmixture 243 was subjected to chiral separation on a Chiralpak AD, 4.6×50mm, 3 mm column (mobile phase 45% isopropanol (w/0.1% triethylamine)/55%CO₂, flow rate 5 mL/min) at 40° C. to give individual enantiomers, with290 eluting first: MS (ESI+) m/z 611.5 (M+H) and Example 291 elutinglast: MS (ESI+) m/z 611.5 (M+H).

Example 29210-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one292 Example 292a10-[5-Fluoro-2-(acetoxymethyl)-3-(1-methyl-5-{[6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one292a

In a 10-mL microwave reaction vessel equipped with a magnetic stirringbar were placed5-bromo-1-methyl-3-(6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one219a (250 mg, 0.64 mmol),10-[2-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one230a (635 mg, 1.3 mmol), Pd(PPh₃)₄ (37 mg, 0.03 mmol) in 2 N Na₂CO₃ (2mL) and 1,2-dimethoxyethane (2 mL). After the reaction mixture wasstirred at 125° C. for 10 minutes, it was purified by flashchromatography (dichloromethane:methanol, 3:1) to give 12% (50 mg) of292a as a solid.

A 25-mL, single-necked, round-bottomed flask equipped with a magneticstirring bar was charged with 292a (50 mg, 0.078 mmol), LiOH.H₂O (50 mg,1.2 mmol), THF (2 mL), i-PrOH (2 mL), and water (2 mL). After thereaction mixture was stirred at room temperature for 2 h, it waspartitioned between dichloromethane (5 mL) and water (5 mL), and theorganic phase was extracted with dichloromethane (5 mL×3). The combinedorganic phases were washed with water (5 mL×2) and brine (5 mL×1), dried(Na₂SO₄), and concentrated. The crude product was re-dissolved indichloromethane (3 mL). To this solution was added hexane (10 mL) andthe resulting precipitates were filtered to give 12% yield (6 mg) of 292MS(ESI⁺) m/z 639.5 (M+H).

Example 2932-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(1-methylazetidin-3-yloxy)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one293 Example 293a4-Fluoro-2-(1-methyl-5-(5-(1-methylazetidin-3-yloxy)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 293a

A mixture of5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yloxy)pyridin-2-ylamino)pyridine-2(1H)-one199f (200 mg, 0.55 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (270 mg, 0.56 mmol), PdCl₂(dppf) (40 mg, 0.055 mmol), K₃PO₄(150 mg), NaOAc (50 mg) in MeCN (8 mL) and water (2 mL) was heated at110° C. in a sealed tube for 2 h. The solvent was evaporated in vacuo.The residue was purified on reverse phase Combi-flash to give 293a (307mg, 70%). MS: [M+H]⁺ 641.

A mixture of 293a (287 mg, 0.45 mmol) and LiOH hydrate (188 mg, 4.5mmol) in isopropanol (25 mL) and water (5 mL) was stirred at 30° C. for2 h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (20 mL×2). The combined extracts were concentratedunder reduced pressure. And the residue was purified on prep-HPLC togive 293 (60 mg, 25%). MS: [M+H]⁺ 599. ¹H NMR (500 MHz, CDCl3) δ 8.51(s, 1H), 7.81 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 7.16-7.14 (m, 1H),7.11-7.09 (m, 1H), 6.95-6.93 (m, 1H), 6.86 (s, 1H), 6.79 (d, J=9.0, 1H),4.76-4.72 (m, 1H), 4.53 (d, J=8.5, 1H), 4.34-4.25 (m, 2H), 4.20-4.13 (m,3H), 3.95-3.84 (m, 3H), 3.69 (s, 3H), 3.24-3.13 (m, 2H), 2.64-2.52 (m,4H), 2.46 (s, 3H), 1.93-1.84 (m, 2H), 1.81-1.75 (m, 2H).

Example 29410-[5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one294 Example 294a(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-10-yl}-4-fluoro-6-(4-methyl-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)methylAcetate 294a

Following Example 150b, 282c and(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 230a were reacted to give 294a in 81% yield. LCMS: (M+H)⁺ 667

Following Example 150, 294a was converted to 294 in 47% yield. LCMS:(M+H)⁺ 625. ¹H NMR (500 MHz, DMSO) δ 9.20 (s, 1H), 7.89 (s, 1H), 7.87(s, 1H), 7.48 (s, 1H), 7.36 (dd, J=10, 1H), 7.31 (dd, J=9.5, 1H), 7.17(s, 1H), 7.15 (s, 1H), 6.52 (s, 1H), 4.85 (m, 1H), 4.49 (m, 1H), 4.40(m, 1H), 4.20 (m, 2H), 4.12 (m, 1H), 3.87 (m, 1H), 3.54 (s, 3H), 2.84(d, J=10.5, 1H), 2.57 (s, 2H), 2.42 (s, 2H), 2.38 (m, 1H), 2.18 (s, 3H),1.93 (t, J=9, 2H), 1.66 (m, 4H), 1.22 (s, 6H).

Example 29510-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one295 Example 295a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl)methylAcetate 295a

A sealed tube was charged with the mixture of5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one282c (350 mg, 0.93 mmol),(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b (448 mg, 0.93 mmol), Pd(dppf)Cl₂ (76 mg, 0.09 mmol),K₃PO₄.3H₂O (495 mg, 1.86 mmol), and NaOAc (153 mg, 1.86 mmol) in CH₃CN(20 mL). The system was evacuated and then refilled with N₂. And thereaction mixture was heated at 110° C. for 2 h. The mixture was cooledto room temperature and filtered. The filtrate was concentrated underreduced pressure and the resulting residue was purified by flash columnchromatography eluting with 15:1 methylene chloride/methanol to give295a as a brown solid (300 mg, 47%). MS: [M+H]⁺ 684

A solution of 295a (250 mg, 0.37 mmol) in propan-2-ol (8 mL),tetrahydrofuran (8 mL) and water (1 mL) was added LiOH (878 mg, 37 mmol)was stirred at 30° C. for 2 h. It was then evaporated and the residuewas purified by prep-HPLC to afford 295 as a yellow solid (76 mg, 32%).MS: (M+H)⁺ 642. ¹H NMR (500 MHz, MEOD) δ 1.29 (d, 6H), 1.94-2.02 (m,2H), 2.18 (d, 2H), 2.56-2.64 (m, 2H), 2.81 (s, 2H), 2.94-3.03 (m, 5H),3.08-3.19 (m, 3H), 3.66 (d, 1H), 3.74 (s, 3H), 3.92-3.97 (m, 1H),4.14-4.19 (m, 1H), 4.50 (s, 1H), 7.21-7.28 (m, 2H), 7.84 (s, 1H), 7.95(d, 1H), 8.13 (s, 1H).

Example 29610-{3-[5-({5-[2-(Dimethylamino)ethoxy]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-5-fluoro-2-(hydroxymethyl)phenyl}-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one296 Example 296a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-6-[5-({5-[2-(dimethylamino)ethoxy]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-4-fluorophenyl)methylAcetate 296a

A mixture of5-bromo-3-(5-(2-(dimethylamino)ethoxy)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one268c (244 mg, 0.67 mmol),(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b (342 mg, 0.67 mmol), PdCl₂(dppf) (59 mg, 0.08 mmol), K₃PO₄(150 mg), and NaOAc (50 mg) in MeCN (6 mL) and water (2 mL) was heatedat 110° C. in a sealed tube for 2 h. The solvent was evaporated in vacuoand the residue was purified on reverse phase Combi-flash to give 296a(287 mg, 60%). MS: [M+H]⁺ 674.

A mixture of 296a (186 mg, 0.28 mmol) and LiOH hydrate (116 mg, 2.8mmol) in isopropanol (25 mL) and water (5 mL) was stirred at 30° C. for2 h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (20 mL×2). The combined extracts were concentratedunder reduced pressure and the residue was purified on prep-HPLC to give296 (126 mg, 71%). MS: [M+H]⁺ 632.

Example 2972-(3-(5-(5-(2-(Dimethylamino)ethoxy)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one297 Example 297a2-(5-(5-(2-(Dimethylamino)ethoxy)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 297a

A mixture of5-bromo-3-(5-(2-(dimethylamino)ethoxy)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one268c (205 mg, 0.56 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (270 mg, 0.56 mmol), PdCl₂(dppf) (51 mg, 0.07 mmol), K₃PO₄(100 mg), and NaOAc (40 mg) in MeCN (6 mL) and water (2 mL) was heatedat 110° C. in a sealed tube for 2 h. The solvent was evaporated invacuo. The residue was purified on reverse phase Combi-flash to give297a (206 mg, 50%). MS: [M+H]⁺ 643.

A mixture of 297a (186 mg, 0.29 mmol) and LiOH hydrate (122 mg, 2.9mmol) in isopropanol (15 mL) and water (3 mL) was stirred at 30° C. for2 h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (20 mL×2). The combined extracts were concentratedunder reduced pressure and the residue was purified on prep-HPLC to give297 (84 mg, 48%). MS: [M+H]⁺ 601. ¹H NMR (500 MHz, CDCl3) δ 8.53 (d,J=2.5, 1H), 7.94 (d, J=3.0, 1H), 7.80 (s, 1H), 7.47 (d, J=2.0, 1H),7.23-7.21 (m, 1H), 7.16-7.14 (m, 1H), 6.95-6.93 (m, 1H), 6.86 (s, 1H),6.81 (d, J=9.0, 1H), 4.55 (d, J=10.5, 1H), 4.40-4.26 (m, 2H), 4.22-4.15(m, 3H), 4.15-4.04 (m, 2H), 3.94-3.86 (m, 1H), 3.69 (s, 3H), 2.75-2.73(m, 2H), 2.62-2.54 (m, 4H), 2.37 (s, 6H), 1.92-1.86 (m, 2H), 1.82-1.76(m, 2H).

Example 29810-[5-fluoro-2-(hydroxymethyl)-3-(4-methyl-6-{[4-(1-methylazetidin-3-yl)phenyl]amino}-5-oxopyrazin-2-yl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one298 Example 298a tert-Butyl 3-(4-Aminophenyl)azetidine-1-carboxylate298a

A mixture of tert-butyl 3-iodoazetidine-1-carboxylate (1 g, 3.53 mmol),4-aminophenylboronic acid (630 mg, 4.59 mmol), NiI₂ (66 mg, 0.212 mmol),NaHMDS (1.94 g, 10.6 mmol), (1R,2S)-2-aminocyclohexanol (24 mg, 0.212mmol) in isopropanol (8 mL) was stirred at 150° C. in microwave for 2 h.It was then evaporated and the residue was dissolved with water andethyl acetate. The water phase was separated and extracted with ethylacetate. The combined extracts were dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified withcolumn chromatography to give 298a (360 mg, 40%). MS: [M+H]⁺ 249.

Example 298b tert-Butyl3-(4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)azetidine-1-carboxylate298b

A mixture of 298a (500 mg, 2.02 mmol),3,5-dibromo-1-methylpyrazin-2(1H)-one (536 mg, 2.02 mmol) andtriethylamine (0.6 mL, 4.04 mmol) in isopropanol (10 mL) was heated atreflux for 4 days. The solvent was evaporated in vacuo and the residuewas purified on reverse phase Combi-flash to afford 298b (690 mg, 66%).MS: [M+H]⁺ 435.

Example 298c3-(4-(Azetidin-3-yl)phenylamino)-5-bromo-1-methylpyrazin-2(1H)-oneHydrochloride 298c

A mixture of 298b (690 mg, 1.6 mmol) and HCl/1,4-dioxane (8M, 8 mL) inmethanol (30 mL) was stirred at room temperature overnight. The mixturewas evaporated in vacuo and the residue was purified on reverse phaseCombi-flash to give 298c (100 mg, 17%). MS: [M+H]⁺ 335.

Example 298d5-Bromo-1-methyl-3-(4-(1-methylazetidin-3-yl)phenylamino)pyrazin-2(1H)-one298d

A mixture of 298c (100 mg, 0.24 mmol), NaBH(OAc)₃ (100 mg, 0.48 mmol),HCHO (10 mL) and acetic acid (1 mL) in methanol (15 mL) was stirred atroom temperature for 4 h. The solvent was evaporated in vacuo and theresidue was neutralized with NaHCO₃ solution until pH 8 was reached. Themixture was extracted with ethyl acetate. The combined extracts weredried over sodium sulfate and concentrated under reduced pressure togive 298d (100 mg), which was used for the next step without furtherpurification. MS: [M+H]⁺ 349.

Example 298e(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4-methyl-6-{[4-(1-methylazetidin-3-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)methylAcetate 298e

To a sealed tube was charged a mixture of(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylAcetate 247b (100 mg, 0.19 mmol),5-bromo-1-methyl-3-(4-(1-methylazetidin-3-yl)phenylamino)pyrazin-2(1H)-one298d (68 mg, 0.19 mmol), PdCl₂(dppf) (14 mg, 0.019 mmol), K₃PO₄ (60 mg),and NaOAc (30 mg) in MeCN (5 mL) and water (1 mL). It was heated at 110°C. for 2 h. The solvent was evaporated in vacuo and the residue waspurified on reverse phase Combi-flash to give 298e (100 mg, 82%). MS:[M+H]⁺ 656.

A mixture of 298e (100 mg, 0.16 mmol) and LiOH hydrate (66 mg, 1.6 mmol)in isopropanol (10 mL) and water (2 mL) was stirred at 30° C. for 2 h.The mixture was evaporated in vacuo and the residue was extracted withethyl acetate (2×20 mL). The combined extracts were concentrated underreduced pressure. And the residue was purified on pre-HPLC to give 298(60 mg, 63%). MS: [M+H]⁺ 614. ¹H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H),7.72 (d, J=7.5, 2H), 7.55 (s, 1H), 7.45-7.43 (m, 1H), 7.30 (s, 1H),7.01-6.99 (m, 1H), 4.56 (d, J=11.5, 1H), 4.41-4.30 (m, 2H), 4.10-4.05(m, 1H), 3.90-3.85 (m, 1H), 3.82-3.72 (m, 2H), 3.64 (s, 3H), 3.22-3.10(m, 2H), 3.04-2.97 (m, 1H), 2.93-2.88 (m, 1H), 2.79 (s, 2H), 2.57-2.50(m, 2H), 2.39 (s, 3H), 1.27 (s, 6H).

Example 29910-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-[1-(oxetan-3-yl)piperidin-4-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one299

Following Example 121b, compound 247b (256 mg, 0.5 mmol),5-bromo-1-methyl-3-(5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one264e (210 mg, 0.5 mmol), 1M sodium carbonate solution (2 mL, 2 mmol),tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and1,2-dimethoxyethane (5 mL) were reacted. The reaction mixture was heatedat 130° C. for 15 minutes in the microwave reactor. Work-up and flashcolumn chromatography (silica, 9:1 methylene chloride/methanol) give amixture of compound 299a and 299 as yellow oil.

The above residue (0.5 mmol) was deprotected using the same procedure as121, except using a mixture of THF (2 mL), water (1 mL) and isopropanol(2 mL and lithium hydroxide monohydrate (105 mg, 2.5 mmol). Work-up andflash column chromatography (NH-silica, ethyl acetate/hexanes) give a12% yield (40 mg) of 299 as a pale yellow solid: MS (ESI+) m/z 684.5(M+H).

Example 30010-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-[1-(oxetan-3-yl)piperidin-4-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0²⁶]dodeca-1(8),2(6)-dien-9-one300 Example 300a5-Bromo-3-(2-methoxypyrimidin-4-ylamino)-1-methylpyridin-2(1H)-one 300a

Following Example 121a, 2-methoxypyrimidin-4-amine (0.625 g, 5 mmol),3,5-dibromo-1-methyl-1H-pyridin-2-one (1.34 g, 5 mmol), cesium carbonate(4.88 g, 15 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.465 g,0.5 mmol), Xantphos (0.58 g, 1 mmol) and 1,4-dioxane (50 mL) werereacted. The reaction mixture was heated at 100° C. for 24 hours, thencool to room temperature, and filtered through a pad of Celite 521. Thefilter cake was washed with 9:1 methylene chloride/methanol (2×25 mL),and the combined filtrates were concentrated to dryness. The residue wasdissolve in methylene chloride, diethyl ethyl was added, and theresulting precipitate was filtered to give a quantitative yield (1.57 g)of 300a as a green solid: MS (ESI+) m/z 313.1 (M+H).

Example 300b10-[5-Fluoro-2-(acetoxymethyl)-3-[1-methyl-5-({5-[1-(oxetan-3-yl)piperidin-4-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one300b

Following Example 121b, 300a (242 mg, 0.5 mmol), 230a (210 mg, 0.5mmol), 1M sodium carbonate solution (2 mL, 2 mmol),tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and1,2-dimethoxyethane (5 mL). The reaction mixture was heated at 130° C.for 15 minutes in the microwave reactor. Work-up and flash columnchromatography (silica, 60:35:5 methylene chloride/diethylether/methanol) give a 67% yield (200 mg) of 300b as a yellow solid: MS(ESI+) m/z 602.4 (M+H).

Following Example 121, a mixture of THF (2 mL), water (1 mL) andisopropanol (2 mL), 300b (200 mg, 0.33 mmol) and lithium hydroxidemonohydrate (105 mg, 2.5 mmol). Work-up and flash column chromatography(NH-silica, Ethyl Acetate/Hexanes) give a 29% yield (55 mg) of compound300 as a white solid: MS (ESI+) m/z 559.4 (M+H).

Example 3012-(2-(Hydroxymethyl)-3-(1-methyl-6-oxo-5-(5-(piperazin-1-yl)pyridin-2-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one301 Example 301a tert-Butyl4-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)piperazine-1-carboxylate301a

To a round-bottomed flask equipped with a stirring bar, tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (2.00 g, 7.18 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (2.87 g, 10.77 mmol), Pd₂(dba)₃(657 mg, 0.718 mmol), XantPhos (665 mg, 1.15 mmol), Cs₂CO₃ (7.72 g, 23.7mmol) and dioxane (40 mL) were added. The reaction mixture was heated at100° C. for 40 hrs. Ethyl acetate (200 mL) was added and the resultingmixture was washed with water (30 mL×3), brine (30 mL×1), dried overMgSO₄, filtered, and removed solvent in vacuo. Methylene chloride/ether(1:2, 5 mL) was added followed by sonication, the precipitate wasfiltered as 301a, yellow solids, 1.946 g (58%).

Example 301b tert-Butyl4-(6-(5-(2-(Acetoxymethyl)-3-(1-oxo-3,4,6,7,8,9-hexa-hydropyrazino[1,2-a]indol-2(1H)-yl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)piperazine-1-carboxylate301b

To a microwave tube equipped with a stirring bar, 301a (500 mg, 1.077mmol),2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one114a (546 mg, 1.292 mmol), Pd(PPh₃)₄(62 mg, 0.054 mmol), Na₂CO₃ aqueoussolution (1.0 N, 3.55 mL, 3.55 mmol), 1,2-dimethoxyethane (4.3 mL) wereadded. The mixture was reacted in microwave at 130° C. for 10 min.Methylene chloride (200 mL) was added and the resulting mixture waswashed with water (3×30 mL), brine (30 mL), dried over MgSO₄, filtered,and removed solvent in vacuo. Silica gel column chromatography(methanol:methylene chloride=5:95) gave 301b.

To a round-bottomed flask equipped with a stirring bar, 301b, methylenechloride (10 mL) was added. The solution was cooled to 0° C. in anice-water bath. TFA (1 mL) was added and the resulting solution wasstirred overnight. Removed all the volatiles in vacuo, and to the bottleTHF (5 mL), isopropanol (5 mL), H₂O (5 mL), LiOH monohydrate (300 mg)were added. The resulting mixture was stirred at RT for 1 hr. Removedall the solvent in vacuo and the resulting residue was added tomethylene chloride (200 mL), the solution was washed with water (3×30mL), brine (30 mL), dried over MgSO₄, filtered, and removed solvent invacuo. Silica gel column (methanol:methylene chloride=10:90) followed byprep-HPLC gave 301 as a yellow solid, 9 mg. MS (ESI+) m/z 580.4 (M+H).

Example 30210-(3-{5-[(1-Ethyl-5-methyl-1H-pyrazol-3-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-5-fluoro-2-(hydroxymethyl)phenyl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one302 Example 302a5-Bromo-3-(1-ethyl-5-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one302a

A sealed tube was equipped with a magnetic stirrer and charged with1-ethyl-5-methyl-1H-pyrazol-3-amine (870 mg, 7 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (1.9 g, 7 mmol) and cesiumcarbonate (5 g, 15 mmol) in 1,4-dioxane (69 mL). After bubbling nitrogenthrough the solution for 30 min, Xantphos (480 mg, 0.8 mmol) andtris(dibenzylideneacetone)dipalladium(0) (450 mg, 0.5 mmol) were added,and the reaction mixture was heated to 100° C. for 16 h. After thistime, water (50 mL) and ethyl acetate (50 mL) were added. The aqueouslayer was separated and extracted with ethyl acetate (2×50 mL). Thecombined organic extracts were washed with brine (100 mL) and dried oversodium sulfate. The mixture was concentrated under reduced pressure tonear dryness when the desired product crashed out and was filtered.Washing with diethyl ether (10 mL) afforded a 40% yield (870 mg) of302a.

Example 302b10-(3-{5-[(1-Ethyl-5-methyl-1H-pyrazol-3-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-5-fluoro-2-(acetoxymethyl)phenyl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one302b

A microwave tube equipped with a magnetic stirrer was charged with 302a(170 mg, 0.5 mmol), 230a (350 mg, 0.7 mmol), 1,2-dimethoxyethane (4 mL)and 1M aqueous sodium carbonate (1.6 mL). After bubbling N₂ for 15 min,Pd(PPh₃)₄ (31 mg, 0.03 mmol) was added. The mixture was heated inmicrowave to 130° C. for 15 min. After this time, ethyl acetate (5 mL)and water (5 mL) were added. The separated aqueous layer was extractedwith ethyl acetate (2×5 mL). The combined organics were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography eluting with a gradient of methylene chloride—60:35:5methylene chloride:diethyl ether:methanol to afford a 60% yield (190 mg)of 302b.

A 25 mL round bottom flask with a magnetic stirrer was charged with 302b(190 mg, 0.3 mmol), lithium hydroxide (70 mg, 1.6 mmol), THF (1.6 mL),isopropanol (1.6 mL) and water (3.2 mL). The mixture stirred at roomtemperature for 2 h. After this time, ethyl acetate (5 mL) and water (5mL) were added. The separated aqueous layer was extracted with ethylacetate (2×5 mL). The combined organics were washed with brine (10 mL),dried over sodium sulfate and filtered. The mixture was concentratedunder reduced pressure to near dryness when the desired product crashedout and was filtered. Upon washing with diethyl ether (10 mL) afforded a51% yield (90 mg) of 302. MS (ESI+) m/z 559.4 (M+H).

Example 3035-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-[1-(oxetan-3-yl)piperidin-4-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one303

Following Example 299, compound 212b was converted to 303. MS (ESI+) m/z670.3 (M+H).

Example 30410-[5-Fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one304

To a solution of(2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-10-yl}-4-fluoro-6-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl)methylacetate (200 mg, 0.28 mmol) in THF/iPA/H₂O (6 mL/6 mL/2 mL) at roomtemperature was added LiOH (70 mg, 2.9 mmol) while stirring. Thismixture was stirred for 0.5 h. Then, 20 mL H₂O was added and the mixturewas extracted with ethyl acetate (30 mL×3). The combined organic layerswere dried with Na₂SO₄ and concentrated to give a yellow solid which wasfurther purified by prep-HPLC to afford 304 as a white solid (100 mg,53%). LCMS: [M+H]⁺ 668. ¹H NMR (500 MHz, DMSO): δ 1.23 (s, 6H),2.37-2.39 (m, 5H), 2.53-2.57 (m, 2H), 3.07 (s, 4H), 3.43-3.45 (m, 2H),3.60 (s, 3H), 3.85-3.87 (m, 1H), 4.16-1.19 (m, 3H), 4.32 (d, J=6.0 Hz,2H), 4.45-4.50 (m, 2H), 4.54-4.58 (m, 2H), 4.86 (s, 1H), 6.47-6.51 (m,1H), 7.18-7.25 (m, 2H), 7.34-7.39 (m, 3H), 7.83-7.86 (m, 1H), 8.35-8.37(m, 1H), 8.53-8.56 (m, 1H).

Example 3055-[2-(Hydroxymethyl)-3-[4-methyl-6-({4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one305 Example 305a{2-[4-Methyl-6-({4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl}methylAcetate 305a

Following Example 136e,5-bromo-1-methyl-3-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)pyrazin-2(1H)-one214b and(2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 111a afforded 305a in 68% yield. LCMS: (M+H)⁺ 694

Following Example 136, 305a was converted to 305 in 51% yield. LCMS:(M+H)⁺ 652. ¹H NMR (500 MHz, DMSO) δ 9.18 (s, 1H), 7.88 (s, 1H), 7.86(s, 1H), 7.52 (d, J=7.5, 1H), 7.46 (t, J=7.5, 1H), 7.38 (s, 1H), 7.17(s, 1H), 7.32 (d, J=7.5, 1H), 7.15 (d, J=8.5, 2H), 4.78 (m, 1H), 4.52(m, 3H), 4.43 (m, 3H), 4.01 (m, 1H), 3.87 (m, 1H), 3.54 (s, 3H), 3.37(m, 1H), 2.96 (m, 1H), 2.86 (m, 1H), 2.78 (m, 4H), 2.43 (m, 2H), 1.82(s, 6H), 1.72 (m, 2H), 1.60 (m, 2H).

Example 30610-[2-(Hydroxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridazin-3-yl]phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one306 Example 306b10-[2-(Acetoxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridazin-3-yl]phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one306b Step 1

In a pressure flask was placed5-chloro-1-methyl-3-(pyrimidin-4-ylamino)pyridazin-2(1H)-one (300 mg,1.26 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(577 mg, 2.27 mmol), potassium acetate (247 mg, 2.32 mmol), X-Phos(2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) (120 mg, 20 mol%), and Tris(dibenzylideneacetone)dipalladium(0) (115 mg, 10 mol %) Theflask was evacuated and filled with N₂ 3×, dioxane (12 mL) was added,the vessel sealed and heated to 90° C. for 2 hrs. The reaction wasallowed to cool then diluted with ethyl acetate, and filtered through apad of celite and concentrated under reduced pressure to give 306a whichwas used directly in the next step.

Step 2

306a was dissolved in dioxane (7 mL) and transferred to a pressure flaskcontaining 189a (448 mg, 1.0 mmol), 10% K₂CO₃/water (2.5 ml) andbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(45 mg, 5 mol %). The flask was sealed and heated to 100° C. overnight.The reaction was then diluted with ethyl acetate and water, separated,washed with brine 3×, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by chromatography: ISCO24 g silica, eluting with 50-100% ethyl acetate/hexanes, to give 306b(250 mg, 35% yield over 2 steps).

Following Example 119, 306b (250 mg, 0.44 mmol), 1N LiOH (2.2 mL), THF(4.5 mL) and isopropanol (4.5 mL) were reacted. The product wastriturated with ether and dried under vacuum to give 306 (185 mg, 80%yield) as an off-white solid. MS (ESI+) m/z 529.3 (M+H).

Example 3072-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one307 Example 307a6-Chloro-2-methyl-4-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridazin-3(2H)-one307a

Following Example 119b, 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one(1.5 g, 6.7 mmol), 5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamine (1.3 g,6.7 mmol), cesium carbonate (4.8 g, 39.4 mmol), and Xantphos (330 mg,8.5 mol %), dioxane (50 ml) and tris(dibenzylideneacetone)dipalladium(0)(307 mg, 5 mol %) were reacted. Purified via column chromatography: ISCO40 g silica, 50-100% ethyl acetate/hexanes then 0-10% methanol to give307a (1.2 g, 53%) as a light tan solid.

Example 307c2-(2-(Acetoxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one307c

Following Example 306b, 307a (422 mg, 1.26 mmol) was converted to theboron intermediate 307b, which was coupled under Suzuki conditions with109a (420 mg, 1.0 mmol). The crude product was purified via columnchromatography: ISCO 24 g silica, 50-100% ethyl acetate/hexanes then0-10% MeOH, to give 307c (285 mg, 36% yield).

Following Example 119, 307c (285 mg, 0.45 mmol), 1N LiOH (2.2 mL), THF(5 mL) and isopropanol (5 mL) were reacted, triturated with ethylacetate and dried under vacuum to give 307 (115 mg, 43% yield) asslightly yellow solid. MS (ESI+) m/z 595.6 (M+H).

Example 3085-[5-Fluoro-2-(Hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylpyrrolidin-3-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one308

Following Example 270, reaction of boronate 212b with bromide 202ayielded 308. MS (ESI+) m/z 614.3 (M+H).

Example 3095-[2-(Hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2-yl}phenyl]-1-methyl-3-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-ylamino}-1,2-dihydropyridin-2-one309

Following Example 270, reaction of boronate 113a with bromide 110cyielded 309. MS (ESI+) m/z 541.2 (M+H).

Example 3103-{[5-(4-Ethylpiperazin-1-yl)pyridine-2-yl]amino}-5-[2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2-yl}phenyl]-1-methyl-1,2-dihydropyridin-2-one310

Following Example 270, reaction of boronate 113a with bromide 138cyielded 310. MS (ESI+) m/z 608.3 (M+H).

Example 31110-[2-(Hydroxymethyl)-3-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one311 Example 311a(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-10-yl}-6-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl)methylAcetate 311a

A sealed tube was charged with the mixture of(2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate (335 mg, 0.7 mmol),5-bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one188e (294 mg, 0.7 mmol), Pd(dppf)Cl₂ (33 mg, 0.04 mmol), K₃PO₄.3H₂O (372mg, 1.4 mmol), and NaOAc (115 mg, 1.4 mmol) in CH₃CN (20 mL). The systemwas evacuated and refilled with N₂. The reaction mixture was heated at110° C. for 2 h. It was then cooled to room temperature and filtered.The filtrate was concentrated under reduced pressure and the resultingresidue was purified by flash column chromatography eluting with 30:1methylene chloride/methanol to afford 311a as a yellow solid (208 mg,43%). MS: [M+H]⁺ 692.

At room temperature, to the solution of 311a (200 mg, 0.29 mol) inTHF/isopropanol/water (6 mL/6 mL/2 mL) was added LiOH (70 mg, 2.9 mmol)while stirring. This mixture was stirred for 0.5 h. Then, 20 mL waterwas added and the mixture was extracted with ethyl acetate (3×30 mL).The combined organic layer was dried with Na₂SO₄ and concentrated togive a yellow solid which was further purified by prep-HPLC to afford311 as a white solid (100 mg, 53%). LCMS: [M+H]⁺ 650. ¹H NMR (500 MHz,DMSO) δ 1.22 (s, 6H), 2.37-2.42 (m, 6H), 2.54-2.56 (m, 1H), 3.06 (d,J=4.5 Hz, 4H), 3.41-3.44 (m, 2H), 3.59 (s, 3H), 3.85-3.90 (m, 1H),4.08-4.21 (m, 3H), 4.35 (d, J=4.5 Hz, 2H), 4.45-4.47 (m, 2H), 4.54-4.57(m, 2H), 4.84-4.86 (m, 1H), 6.45 (s, 1H), 7.22 (d, J=9.0 Hz, 1H),7.31-7.47 (m, 4H), 7.44-7.47 (m, 1H), 7.86 (d, J=3.0 Hz, 1H), 8.37 (s,1H), 8.56 (d, J=2.0 Hz, 1H).

Example 31210-[2-(Hydroxymethyl)-3-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one 312 Example 312a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-6-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl)methylAcetate 312a

Following Example 136e,5-bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one(24-7) and(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 131a was converted to 312a in 63% yield. LCMS: (M+H)⁺ 709

Following Example 136, 312a was converted to 312 in 60% yield. LCMS:(M+H)⁺ 667. ¹H NMR (500 MHz, MEOD) δ 8.52 (s, 1H), 7.93 (m, 1H), 7.50(m, 1H), 7.42 (m, 3H), 7.30 (s, 1H), 7.05 (m, 1H), 4.73 (t, J=6.5, 2H),4.64 (t, J=6, 2H), 4.56 (m, 2H), 4.14 (m, 1H), 3.98 (m, 1H), 3.71 (s,3H), 3.67 (m, 1H), 3.16 (m, 4H), 3.11 (m, 1H), 2.96 (m, 1H), 2.81 (s,2H), 2.60 (m, 2H), 2.53 (s, 4H), 1.29 (d, J=3, 6H).

Example 3135-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(2S)-(1-methylpyrrolidin-2-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one313 Example 3145-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(2R)-(1-methylpyrrolidin-2-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one314

Compounds 313 and 314 are enantiomers of racemate 288. The racemicmixture 288 was subjected to chiral separation on a Chiralpak AD, 4.6×50mm, 3 mm column (mobile phase 55% isopropanol (w/0.1% triethylamine)/45%CO₂, flow rate 5 mL/min) at 40° C. to give individual enantiomers, with313 eluting first, and 314 eluting last.

Example 3155-[2-(Hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one315 Example 315a[2-(1-Methyl-5-{[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl]methylAcetate 315a

A sealed tube was charged with the mixture of5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one130c (400 mg, 1.06 mmol),(2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 111a (512 mg, 1.06 mmol), Pd(dppf)Cl₂ (87 mg, 0.1 mmol),K₃PO₄.3H₂O (566 mg, 2.12 mmol), and NaOAc (174 mg, 2.12 mmol) in CH₃CN(25 mL). The system was evacuated and then refilled with N₂. Thereaction mixture was heated at 110° C. for 2 h. Then, the mixture wascooled to room temperature and filtered. The filtrate was concentratedunder reduced pressure and the resulting residue was purified by flashcolumn chromatography eluting with 10:1 methylene chloride/methanol togive 315a as a brown solid (300 mg, 43%). MS: [M+H]⁺ 652

A solution of 315a (250 mg, 0.38 mmol) in propan-2-ol (10 mL),tetrahydrofuran (10 mL) and water (1.5 mL) was added LiOH (922 mg, 38mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by reverse phase Combi-flash eluting with0.3% NH₄HCO₃ in 1:4 water/CH₃CN to give 315 as a white solid (37 mg,16%). MS: (M+H)⁺ 610. ¹H NMR (500 MHz, MeOD) δ 1.74-1.84 (m, 4H),1.87-1.95 (m, 4H), 2.13-2.18 (t, J=11.5, 2 H), 2.32 (s, 3H), 2.52-2.61(m, 3H), 2.85-2.87 (t, J=4.5, 2 H), 2.92-3.06 (m, 4H), 3.71 (s, 3H),3.99-4.03 (m, 1H), 4.12-4.17 (m, 1H), 4.52-4.59 (m, 2H), 7.03 (d, 1H),7.34 (d, 1H), 7.39 (d, 1H), 7.42 (d, 1H), 7.51 (d, 1H), 7.56 (d, 1H),8.08 (s, 1H), 8.62 (s, 1H).

Example 3165-[5-Fluoro-2-(hydroxymethyl)-3-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]-1-methyl-3-[(4-(1-methylazetidin-3-yl)phenyl)amino)-1,2-dihydropyrazin-2-one316 Example 316a4-Fluoro-2-(4-methyl-6-(4-(1-methylazetidin-3-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 316a

A sealed tube was charged with the mixture of5-bromo-1-methyl-3-(4-(1-methylazetidin-3-yl)phenylamino)pyrazin-2(1H)-one298c (200 mg, 0.58 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (280 mg, 0.58 mmol), Pd(dppf)Cl₂ (40 mg, 0.06 mmol),K₃PO₄.3H₂O (300 mg, 1.16 mmol), and NaOAc (100 mg, 1.16 mmol) in CH₃CN(20 mL). The system was evacuated and then refilled with N₂. And thereaction mixture was heated at 110° C. for 3 h. Then, the mixture wascooled to room temperature and filtered. The filtrate was concentratedunder reduced pressure and the resulting residue was purified by flashcolumn chromatography eluting with 15:1 methylene chloride/methanol togive 216a as a brown solid (150 mg, 42%). MS: [M+H]⁺ 625

A solution of 316a (130 mg, 0.21 mmol) in propan-2-ol (7 mL),tetrahydrofuran (7 mL), and water (1 mL) was added LiOH (500 mg, 21mmol). The mixture was stirred at 30° C. for 2 h. It was evaporated andthe residue was purified by prep-HPLC to afford 316 as a white solid (14mg, 12%). MS: (M+H)⁺ 583. ¹H NMR (500 MHz, MEOD) δ 1.77-1.81 (m, 2H),1.89-1.95 (m, 2H), 2.46 (s, 3H), 2.55 (t, J=6, 2 H), 2.60-2.68 (m, 2H),3.64 (s, 3H), 3.73-3.77 (m, 1H), 3.85 (s, 2H), 4.16-4.27 (m, 1H),4.46-4.59 (m, 2H), 6.72 (s, 1H), 7.19-7.21 (d, 1H), 7.8-7.30 (d, 2H),7.31-7.41 (dd, 2H), 7.78 (d, 2H).

Example 31710-[2-(Hydroxymethyl)-3-(1-methyl-5-{[5-(oxetan-3-yl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one317 Example 317a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-6-(1-methyl-5-{[5-(oxetan-3-yl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl)methylAcetate 317a

A sealed tube was charged with the mixture of5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one252a (275 mg, 0.7 mmol),(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 131a (356 mg, 0.7 mmol), Pd(dppf)Cl₂ (59 mg, 0.07 mmol),K₃PO₄.3H₂O (317 mg, 1.4 mmol), and NaOAc (118 mg, 1.4 mmol) in CH₃CN (20mL). The system was evacuated and refilled with N₂. The reaction mixturewas heated at 110° C. for 2 h. It was then cooled to room temperatureand filtered. The filtrate was concentrated under reduced pressure andthe resulting residue was purified by flash column chromatographyeluting with 30:1 methylene chloride/methanol to afford 317a as a yellowsolid (300 mg, 61%). MS: [M+H]⁺ 669.

At room temperature, to the solution of 317a (300 mg, 0.5 mol) inTHF/isopropanol/water (6 mL/6 mL/2 mL) was added LiOH (70 mg, 2.9 mmol)while stirring. This mixture was stirred for 0.5 h. Then, 20 mL H₂O wasadded and the mixture was extracted with ethyl acetate (3×30 mL). Thecombined organic layer was dried with Na₂SO₄ and concentrated to get ayellow solid, which was further purified by prep-HPLC to afford 317 as awhite solid (93 mg, 28%). MS: [M+H]⁺ 627. ¹H NMR (500 MHz, DMSO) δ 1.24(s, 6H), 2.65 (s, 1H), 2.75 (d, J=8.5 Hz, 4H), 2.88-2.91 (m, 1H),3.00-3.03 (m, 1H), 3.50 (s, 2H), 3.57 (s, 3H), 3.67 (t, J=6.0 Hz, 1H),3.84-3.89 (m, 1H), 3.93 (t, J=6.0 Hz, 2H), 4.00-4.05 (m, 1H), 4.34-4.36(m, 2H), 4.49 (t, J=6.0 Hz, 2H), 4.59 (t, J=7.0 Hz, 2H), 4.83 (d, J=5.0Hz, 1H), 5.91 (s, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.24-7.35 (m, 2H), 7.45(t, J=7.0 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.13 (s, 1H).

Example 31810-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(oxetan-3-yl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one318 Example 318a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(1-methyl-5-{[5-(oxetan-3-yl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl)methylAcetate 318a

A sealed tube was charged with the mixture of(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b (300 mg, 0.584 mmol),5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one252a (222 mg, 0.584 mmol), Pd(dppf)Cl₂ (48 mg, 0.0584 mmol), K₃PO₄.3H₂O(311 mg, 1.168 mmol), and NaOAc (96 mg, 1.168 mmol) in CH₃CN (20 mL).The system was evacuated and then refilled with N₂. And the reactionmixture was heated at 110° C. for 2 h. Then, the mixture was cooled toroom temperature and filtered. The filtrate was concentrated underreduced pressure and the resulting residue was purified by flash columnchromatography eluting with 30:1 methylene chloride/methanol to afford318a as a yellow solid (304 mg, 74%). MS: [M+H]⁺ 687.

To a solution of 318a (300 mg, 0.44 mol) in THF/isopropanol/water (6mL/6 mL/2 mL) was added LiOH (100 mg, 4.16 mmol) at room temperature.The mixture was stirred for 0.5 h. Then, 20 mL H₂O was added and themixture was extracted with ethyl acetate (30 mL×3). The combined organiclayer was dried with Na₂SO₄ and concentrated to give a yellow solid,which was further purified by prep-HPLC to afford 318 as a white solid(68.7 mg, 52.3%). ¹H NMR (500 MHz, DMSO) δ 8.17 (s, 1H), 7.98 (d, J=6Hz, 1H), 7.30 (t, 2H), 7.17 (t, 1H), 5.91 (s, 1H), 4.88 (t, 1H), 4.58(t, 2H), 4.48 (t, 2H), 4.32 (d, 1H), 4.05 (t, 1H), 4.02 (m, 3H), 3.94(m, 2H), 3.92 (s, 1H), 3.83 (s, 1H), 3.30 (s, 1H), 3.02 (m, 1H), 2.88(s, 4H), 2.73 (s, 2H), 1.20 (s, 6H)

Example 3192-(2-(Hydroxymethyl)-3-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one319 Example 319a[2-(1-Methyl-5-{[5-(oxetan-3-yl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)-6-{1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-2-yl}phenyl]methylAcetate 319a

A sealed tube was charged with the mixture of5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one252a (265 mg, 0.7mmol),2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 114a (320 mg, 0.7 mmol), Pd(dppf)Cl₂ (56 mg, 0.07 mmol),K₃PO₄.3H₂O (367 mg, 1.4 mmol), and NaOAc (113 mg, 1.4 mmol) in CH₃CN (20mL). The system was evacuated and refilled with N₂. The reaction mixturewas heated at 110° C. for 2 h. It was then cooled to room temperatureand filtered. The filtrate was concentrated under reduced pressure andthe resulting residue was purified by flash column chromatographyeluting with 30:1 methylene chloride/methanol to afford 319a as a yellowsolid (200 mg, 38%). MS: [M+H]⁺ 638.

At room temperature, to the solution of 319a (150 mg, 0.24 mol) inTHF/isopropanol/water (6 mL/6 mL/2 mL) was added LiOH (70 mg, 2.9 mmol)while stirring. This mixture was stirred for 0.5 h. Then, 20 mL waterwas added and the mixture was extracted with ethyl acetate (3×30 mL).The combined organic layer was dried with Na₂SO₄ and concentrated togive a yellow solid, which was further purified by prep-HPLC to afford319 as a white solid (50 mg, 28%). MS: [M+H]⁺ 596. ¹H NMR (500 MHz,DMSO) δ 1.23 (t, J=7.0 Hz, 2H), 1.70-2.08 (m, 5H), 2.74-2.76 (m, 2H),3.50 (s, 2H), 3.57 (s, 3H), 3.67 (s, 1H), 3.91-3.94 (m, 3H), 4.03-4.16(m, 4H), 4.35 (s, 2H), 4.48-4.50 (m, 2H), 4.58-4.60 (m, 2H), 4.61 (s,1H), 5.91 (s, 1H), 6.51 (s, 1H), 7.23 (s, 1H), 7.30-7.34 (m, 2H),7.44-7.47 (m, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.12 (s, 1H).

Example 3202-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one320 Example 320a N-Methyl(1-methyl-3-nitro-1H-pyrazol-5-yl)methanamine320a

To a stirred solution of MeNH₂ (30% wt in H₂O) (2.5 g, 20 mmol) inacetone (10 mL) at 0° C. (ice bath) was added K₂CO₃ (415 mg, 3 mmol),followed by the dropwise addition of a solution of5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (220 mg, 1 mmol) in acetone(5 mL). The reaction mixture was then warmed to room temperature andstirred for 3 h. The solvent was removed and the residue was extractedwith methylene chloride (15 mL×3), dried over Na₂SO₄ and concentrated toafford 320a as a yellow oil (170 mg, 99%), which was used in the nextstep without additional purification. LCMS: (M+H)⁺ 171

Example 320bN-Methyl-N-((1-methyl-3-nitro-1H-pyrazol-5-yl)methyl)oxetan-3-amine 320b

To a mixture of 320a (170 mg, 1 mmol) in methanol (4 mL), ZnCl₂ (1mmol/L in diethyl ether) (2 mL, 2 mmol) and oxetan-3-one (150 mg, 2mmol) were added at room temperature under nitrogen protection, followedby the addition of NaBH₃CN (130 mg, 2 mmol). The reaction mixture waswarmed to 50° C. and stirred for 3 h. The mixture was then cooled toroom temperature and the solvent was removed. The residue was purifiedon flash column eluting with 50:1 methylene chloride/methanol to afford320b as a yellow solid (180 mg, 80%, two steps). LCMS: (M+H)⁺ 227. ¹HNMR (500 MHz, DMSO) δ 6.99 (s, 1H), 4.52 (t, J=6.5, 2H), 4.42 (t, J=6,2H), 3.98 (s, 3H), 3.63 (m, 1H), 3.50 (s, 2H), 2.03 (s, 3H).

Example 320c1-Methyl-5-((methyl(oxetan-3-yl)amino)methyl)-1H-pyrazol-3-amine 320c

To a solution of 320b (1.8 g, 7.96 mmol) in ethanol (20 mL) and water(20 mL), NH₄Cl (3.3 g, 63.6 mmol) and iron powder (1.80 g, 31.8 mmol)were added. The reaction mixture was heated at 70° C. for 2 h. Afterthat, the mixture was cooled to room temperature and filtered. Thefiltrate was evaporated and the residue was extracted with methylenechloride (30 mL×3), dried Na₂SO₄, and concentrated to afford the crudeproduct, which was purified on flash column eluting with 50:1 methylenechloride/methanol containing 0.5% triethylamine to afford 320c as ayellow oil (1.3 g, 83%). LCMS: (M+H)⁺ 197

Example 320d5-Bromo-1-methyl-3-(1-methyl-5-((methyl(oxetan-3-yl)amino)methyl)-1H-pyrazol-3-ylamino)pyridin-2(1H)-one320d

Following Example 136d, 320c and 3,5-dibromo-1-methylpyridin-2(1H)-onewere reacted to give 320d in 63% yield. LCMS: (M+H)⁺ 383. ¹H NMR (500MHz, DMSO) δ 8.35 (s, 1H), 7.99 (d, J=2.5, 1H), 7.36 (d, J=2.5, 1H),5.99 (s, 1H), 4.50 (t, J=7, 2H), 4.40 (t, J=6.5, 2H), 3.77 (s, 3H), 3.57(m, 1H), 3.49 (s, 3H), 3.35 (s, 2H), 2.01 (s, 3H).

Example 320e4-Fluoro-2-(1-methyl-5-(1-methyl-5-((methyl(oxetan-3-yl)amino)methyl)-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 320e

Following Example 136e, 210d was converted to 320e in 71% yield.

Following Example 136, 320e was converted to 320 in 66% yield. LCMS:(M+H)⁺ 616. ¹H NMR (500 MHz, DMSO) δ 8.07 (s, 1H), 7.97 (s, 1H), 7.30(m, 2H), 7.17 (d, J=9.5, 1H), 6.53 (s, 1H), 6.02 (s, 1H), 4.88 (m, 1H),4.50 (t, J=6.5, 2H), 4.40 (t, J=5.5, 2H), 4.32 (s, 2H), 4.14 (m, 3H),3.89 (m, 1H), 3.70 (s, 3H), 3.57 (m, 4H), 2.59 (m, 2H), 2.47 (m, 2H),2.00 (s, 3H), 1.80 (m, 2H), 1.70 (m, 2H).

Example 32110-[5-Fluoro-2-(Hydroxymethyl)-3-{1-methyl-5-[(1-methyl-5-{[methyl(oxetan-3-yl)amino]methyl}-1H-pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one321 Example 321a(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-10-yl}-4-fluoro-6-{1-methyl-5-[(1-methyl-5-{[methyl(oxetan-3-yl)amino]methyl}-1H-pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl)methyl321a

Following Example 136e,5-bromo-1-methyl-3-(1-methyl-5-((methyl(oxetan-3-yl)amino)methyl)-1H-pyrazol-3-ylamino)pyridin-2(1H)-one320d and 230a were reacted to give 321a in 65% yield. LCMS: (M+H)⁺ 672

Following Example 136, 321a was converted to 321 in 59% yield. LCMS:(M+H)⁺ 630. ¹H NMR (500 MHz, DMSO) δ 8.07 (s, 1H), 7.97 (d, J=2.5, 1H),7.33 (d, J=2.5, 1H), 7.31 (d, J=3, 1H), 7.29 (d, J=2, 1H), 7.17 (dd,J=9.5, 1H), 6.51 (s, 1H), 6.02 (s, 1H), 4.89 (t, J=4.5, 1H), 4.50 (t,J=6.5, 2H), 4.40 (t, J=6, 2H), 4.33 (d, J=4.5, 2H), 4.21 (m, 2H), 4.13(m, 1H), 3.88 (m, 1H), 3.70 (s, 3H), 3.57 (m, 4H), 2.57 (s, 2H), 2.42(s, 2H), 2.00 (s, 3H), 1.22 (s, 6H).

Example 32210-[5-Fluoro-2-(hydroxymethyl)-3-{1-methyl-5-[(1-methyl-5-{[methyl(oxetan-3-yl)amino]methyl}-1H-pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one322 Example 322a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-[1-methyl-5-{(1-methyl-5-{[methyl(oxetan-3-yl)amino]methyl}-1H-pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl)methylacetate 322a

A sealed tube was charged with the mixture of5-bromo-1-methyl-3-(1-methyl-5-((methyl(oxetan-3-yl)amino)methyl)-1H-pyrazol-3-ylamino)pyridin-2(1H)-one320d (250 mg, 0.65 mmol),(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b (334 mg, 0.65 mmol), Pd(dppf)Cl₂ (55 mg, 0.07 mmol),K₃PO₄.3H₂O (345 mg, 1.3 mmol), and NaOAc (105 mg, 1.3 mmol) in CH₃CN (20mL). The system was evacuated and refilled with N₂. The reaction mixturewas heated at 110° C. for 2 h. It was then cooled to room temperatureand filtered. The filtrate was concentrated under reduced pressure andthe resulting residue was purified by flash column chromatographyeluting with 30:1 methylene chloride/methanol to afford 322a as a yellowsolid (300 mg, 56%). MS: [M+H]⁺ 689.

At room temperature, to a solution of 322a (250 mg, 0.35 mol) inTHF/isopropanol/water (6 mL/6 mL/2 mL) was added LiOH (70 mg, 2.9 mmol)while stirring. This mixture was stirred for 0.5 h. Then, 20 mL waterwas added and the mixture was extracted with ethyl acetate (30 mL×3).The combined organic layer was dried with Na₂SO₄ and concentrated toyield a yellow solid, which was further purified by prep-HPLC to afford322 as a white solid (94 mg, 36%). MS: [M+H]⁺ 647. ¹H NMR (500 MHz,DMSO) δ 1.23 (s, 6H), 2.01 (s, 3H), 2.50-2.52 (m, 2H), 2.76 (s, 2H),2.88-2.91 (m, 1H), 3.04 (s, 1H), 3.55-3.57 (m, 4H), 3.70 (s, 3H), 3.86(t, J=6.0 Hz, 1H), 4.06 (d, J=5.5 Hz, 1H), 4.33-4.41 (m, 4H), 4.50 (t,J=6.5 Hz, 2H), 4.88 (t, J=5.0 Hz, 1H), 6.02 (s, 1H), 7.16-7.18 (m, 1H),7.29-7.34 (m, 2H), 7.97 (d, J=2.5 Hz, 1H), 8.07 (s, 1H).

Example 32310-[2-(Hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino}-6-oxopyridin-3-yl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-9-one323 Example 323a(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-10-yl}-6-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl)methylAcetate 323a

A 25 mL sealed tube was charged with5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one282c (376 mg, 1.0 mmol),(2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^(2,6)]dodeca-2(6),7-dien-10-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate (478 mg, 1.0 mmol), CH₃COONa (168 mg, 2.0 mmol), K₃PO₄ (546 mg,2.0 mmol), PdCl₂(dppf) (84 mg, 0.1 mmol) suspended in CH₃CN (25 mL) andH₂O (1 mL). The mixture was heated at 110° C. for 2 hours. It was thenevaporated and the residue was purified by column chromatography elutingwith 15:1 methylene chloride/methanol to give 323a as a brown solid (278mg, 43%). MS: (M+H)⁺ 649.

A solution of 323a (200 mg, 0.3 mmol) in propan-2-ol (10 mL),tetrahydrofuran (10 mL) and water (2 mL) was added LiOH (1.1 g, 57mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by prep-HPLC to afford 323 as a white solid(41 mg, 22%). MS: (M+H)⁺ 607. ¹H NMR (500 MHz, DMSO) δ 8.65 (s, 1H),8.50 (s, 1H), 8.05 (s, 1H), 7.51 (m, 2H), 7.46 (m, 3H), 7.31 (d, J=8.5,1H), 6.50 (s, 1H), 4.83 (m, 1H), 4.39 (m, 2H), 4.13 (m, 1H), 3.85 (m,1H), 3.59 (s, 3H), 3.03 (m, 1H), 2.91 (m, 3H), 2.84 (m, 2H), 2.64 (m,1H), 2.46 (m, 1H), 2.17 (s, 3H), 1.80 (m, 2H), 1.60 (m, 4H), 1.22 (s,6H).

Example 3245-[5-Fluoro-2-(hydroxymethyl)-3-{1-methyl-5-[(1-methyl-5-{[methyl(oxetan-3-yl)amino]methyl}-1H-pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-6-one324 Example 324a(4-Fluoro-2-{1-methyl-5-[(1-methyl-5-{[methyl(oxetan-3-yl)amino]methyl}-1H-pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridin-3-yl}-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}phenyl)methylAcetate 324a

A sealed tube was charged with the mixture of5-bromo-1-methyl-3-(1-methyl-5-((methyl(oxetan-3-yl)amino)methyl)-1H-pyrazol-3-ylamino)pyridin-2(1H)-one320d (150 mg, 0.39 mmol),(4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 247b (195 mg, 0.39 mmol), Pd(dppf)Cl₂ (33 mg, 0.04 mmol),K₃PO₄.3H₂O (207 mg, 0.78 mmol), and NaOAc (63 mg, 0.78 mmol) in CH₃CN(20 mL). The system was evacuated and refilled with N₂. The reactionmixture was heated at 110° C. for 2 h. It was then cooled to roomtemperature and filtered. The filtrate was concentrated under reducedpressure and the resulting residue was purified by flash columnchromatography eluting with 30:1 methylene chloride/methanol to afford324a as a yellow solid (150 mg, 56%). MS: [M+H]⁺ 675.

At room temperature, to a solution of 324a (150 mg, 0.22 mol) inTHF/isopropanol/water (6 mL/6 mL/2 mL) was added LiOH (70 mg, 2.9 mmol)while stirring. This mixture was stirred for 0.5 h. Then, 20 mL H₂O wasadded and extracted with ethyl acetate (3×30 mL). The combined organiclayer was dried with Na₂SO₄ and concentrated to get a yellow solid,which was further purified by prep-HPLC to afford 324 as a white solid(43 mg, 31%). MS: [M+H]⁺ 633. ¹H NMR (500 MHz, DMSO) δ 1.75-1.80 (m,4H), 2.00 (s, 4H), 2.85 (s, 4H), 2.36 (s, 1H), 2.64 (s, 1H), 2.78 (s,2H), 2.83-2.89 (m, 1H), 2.94-3.01 (m, 1H), 3.58 (s, 3H), 3.69 (s, 3H),3.86-3.89 (m, 1H), 4.02-4.07 (m, 1H), 4.32 (d, J=3.0 Hz, 2H), 4.39 (t,J=6.5 Hz, 2H), 4.49 (t, J=6.5 Hz, 2H), 4.85 (d, J=4.5 Hz, 1H), 6.01 (s,1H), 7.15-7.18 (m, 1H), 7.28-7.32 (m, 2H), 7.96 (d, J=2.0 Hz, 1H), 8.06(s, 1H).

Example 32510-[2-(Hydroxymethyl)-3-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridine-2-yl]amino}-6-oxopyridin-3-yl)phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-9-one325 Example 325a(2-{4,4-Dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6)-dien-10-yl}-6-(1-methyl-5-{[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino}-6-oxopyridin-3-yl)phenyl)methylAcetate 325a

A 25 mL sealed tube is charged with5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridine-2-ylamino)pyridin-2(1H)-one282c (376 mg, 1.0 mmol),(2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.0^(2,6)}]dodeca-1(8),2(6)-dien-10-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 131a (495 mg, 1.0 mmol), CH₃COONa (168 mg, 2.0 mmol), K₃PO₄ (546mg, 2.0 mmol), PdCl₂(dppf) (84 mg, 0.1 mmol) suspended in CH₃CN (25 mL)and water (1 mL). The mixture was heated at 110° C. for 2 hours. It wasthen evaporated and the residue was purified by column chromatographyeluting with 50:1 methylene chloride/methanol to give 325a as a brownsolid (278 mg, 42%). MS: (M+H)⁺ 666.

A solution of 325a (200 mg, 0.3 mmol) in isopropanol (10 mL), andtetrahydrofuran (10 mL) and water (2 mL) was added LiOH (1.1 g, 57mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by prep-HPLC to afford 325 as a white solid(54 mg, 29%). MS: (M+H)⁺ 624. ¹H NMR (500 MHz, DMSO) δ 8.66 (s, 1H),8.50 (s, 1H), 8.10 (s, 1H), 7.51 (m, 2H), 7.46 (m, 3H), 7.31 (d, J=8.5,1H), 4.83 (m, 1H), 4.39 (m, 2H), 4.13 (m, 1H), 3.85 (m, 1H), 3.59 (s,3H), 3.03 (m, 1H), 2.91 (m, 3H), 2.84 (m, 2H), 2.64 (m, 1H), 2.46 (m,1H), 2.23 (s, 3H), 1.80 (m, 2H), 1.66 (m, 4H), 1.20 (s, 6H).

Example 3262-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one326 Example 326a4-Fluoro-2-(1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylAcetate 326a

Following Examples 102c and 102d, 326a was prepared.

Example 326b4-fluoro-2-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 326b

Following Example 148h, 478 mg of 326a and 378 mg5-bromo-1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one197d were reacted to give 326b was obtained as a yellow solid (324 mg,50%). MS: [M+H]⁺ 650.

Following Example 148, 260 mg of 326b was converted to 326 as a whitesolid (100 mg, 41%). MS: [M+H]⁺ 607. ¹H NMR (500 MHz, DMSO) δ 8.58 (d,J=2.0, 1H), 8.39 (s, 1H), 7.87 (d, J=3.0, 1H), 7.73 (d, J=8.0, 1H), 7.63(d, J=8.0, 1H), 7.46 (dd, J=9.0, 1H), 7.36 (m, 3H), 7.23 (m, 2H), 7.17(m, 2H), 4.99 (d, J=4.5, 1H), 4.65 (m, 1H), 4.50 (m, 1H), 4.38 (s, 2H),4.29 (m, 1H), 4.10 (m, 1H), 3.59 (s, 3H), 3.04 (t, J=4.0, 4H), 4.36 (t,J=4.0, 4H), 2.20 (s, 3H).

Example 3272-(5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one327 Example 327a tert-Butyl 4-(4-Nitrophenyl)piperazine-1-carboxylate327a

Following Example 188a, 1-fluoro-4-nitrobenzene (2.8 g, 20 mmol) andN-Boc-piperazine (11 g, 60 mmol) were reacted to give 327a as a yellowsolid (3 g, 51%). MS: [M+H]⁺ 308.

Example 327b tert-Butyl 4-(4-Aminophenyl)piperazine-1-carboxylate 327b

Following Example 188b, 327a was reduced to 327b as a yellow solid (1.35g, 99%). MS: [M+H]⁺ 278.

Example 327c tert-Butyl4-(4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)piperazine-1-carboxylate327c

Following Example 188c, 327b (2.6 g, 9.4 mmol) and3,5-dibromo-1-methylpyrazin-2(1H)-one (2.5 g, 9.4 mmol) were reacted togive 327c as a yellow solid (2.96 g, 68%). MS: [M+H]⁺ 464.

Example 327d5-Bromo-1-methyl-3-(4-(piperazin-1-yl)phenylamino)pyrazin-2(1H)-one 327d

Following Example 188d, 327c was deprotected to give 327d as a yellowsolid (1.57 g, 99%). MS: [M+H]⁺ 364.

Example 327e5-Bromo-1-methyl-3-(4-(4-(oxetan-3-yl)piperazin-1yl)phenyl-amino)pyrazin-2(1H)-one327e

Following Example 188e, 1.2 g (3 mmol) of 327d was converted to 327e asa yellow solid (943 mg, 75%). MS: [M+H]⁺ 420.

Example 327f4-Fluoro-2-(4-methyl-6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 327f

Following Example 148h, 300 mg of4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d and 287 mg of 327e were reacted to give 327f as a yellowsolid (220 mg, 51%). LCMS: [M+H]⁺ 696

Following Example 148, 220 mg of 327f was converted to 327 as a whitesolid (87 mg, 42%). ¹H NMR (500 MHz, DMSO) δ 9.11 (s, 1H), 7.81 (d,J=8.5, 1H), 7.43 (s, 1H), 7.35 (t, J=7.0, 1H), 7.29 (d, J=9.0, 1H), 6.88(d, J=8.5, 2H), 6.53 (s, 1H), 4.86 (s, 1H), 4.56 (t, J=6.5, 2H), 4.67(d, t=5.5, 3H), 4.42 (m, 1H), 4.11 (m, 3H), 3.89 (m, 1H), 3.53 (s, 3H),3.43 (s, 1H), 3.10 (t, J=4.5, 4H), 2.62 (m, 2H), 2.46 (m, 2H), 2.39 (t,J=4.5, 4H), 1.79 (s, 2H), 1.70 (s, 2H).

Example 3282-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one328 Example 328a4-(6-(6-Chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl-amino)pyridin-3-yl)piperazine-1-carboxylate328a

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 1,4-dioxane (50 mL),tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate 188b (2.0 g,7.2 mmol), 4-bromo-6-chloro-2-methyl-pyridin-3(2H)-one (1.6 g, 7.2 mmol)and cesium carbonate (4.7 g, 14.4 mmol). After bubbling nitrogen throughthe resulting mixture for 30 minutes, XantPhos (500 mg, 0.9 mmol) andtris(dibenzylideneacetone)dipalladium(0) (450 mg, 0.45 mmol) was added,and the reaction mixture was heated at reflux for 3 h. After this timethe reaction was cooled to room temperature, partitioned between ethylacetate (100 mL) and water (100 mL), and filtered. The aqueous layer wasseparated and extracted with ethyl acetate (50 mL×2). The organic layerswere combined, washed with brine (50 mL), and dried over sodium sulfate.The drying agent was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified on flashcolumn eluting with petroleum ether/ethyl acetate to afford 328a (1.4 g,43%). MS: [M+H]⁺ 421

Example 328b6-Chloro-2-methyl-4-(5-(piperazin-1-yl)pyridin-2-ylamino)pyridazin-3(2H)-oneHydrochloride 328b

Intermediate 328a (1.4 g, 3.3 mmol) was suspended in 4.0 M HCl/dioxane(10 mL). The reaction mixture was stirred at room temperature for 2 hand concentrated under reduced pressure to give 328b (1.1 g, 96%). MS:[M+H]⁺ 321.

Example 328c6-Chloro-2-methyl-4-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridazin-3(2H)-one328c

A mixture of 328b (1.2 g, 3.5 mmol), oxetan-3-one (0.5 g, 7.0 mmol),NaBH₃CN (0.44 g, 7.0 mmol) and zinc chloride (0.93 g, 7.0 mmol) inmethanol (125 ml) was stirred at 50 degree for 3.5 hours. The mixturewas added to water and extracted with methylene chloride. The organiclayers were combined and concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 25:1methylene chloride/methanol to give 328c (0.63 g, 50%). MS: [M+H]⁺ 377.

Example 328d4-Fluoro-2-(1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 328d

A sealed tube was charged with the mixture of4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (420 mg, 0.9 mmol), 328c (300 mg, 0.78 mmol), Pd(dppf)Cl₂(66 mg, 0.078 mmol), K₃PO₄.3H₂O (360 mg, 1.56 mmol), and NaOAc (130 mg,1.56 mmol) in CH₃CN (20 ml). The system was evacuated and then refilledwith N₂. And the reaction mixture was heated at 110° C. for 2 h. Then,the mixture was cooled to room temperature and filtered. The filtratewas concentrated under reduced pressure and the resulting residue waspurified by flash column chromatography eluting with 30:1 methylenechloride/methanol to afford 328d as a yellow solid (400 mg, 72%). MS:[M+H]⁺ 696.

To the solution of 328d (350 mg, 0.5 mol) in THF/iPA/H₂O (6 ml/6 ml/2ml) was added LiOH (600 mg, 25 mmol) while stirring at room temperature.And this mixture was stirred for 0.5 h. Then, 20 mL water was added andresulting mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layer was dried with Na₂SO₄ and concentrated to give ayellow solid, which was further purified by prep-HPLC to afford 328 as awhite solid (100 mg, 27%). ¹H NMR (500 MHz, DMSO) δ 9.25 (s, 1H), 8.41(s, 1H), 7.97 (d, J=3.5 Hz, 1H), 7.39-7.45 (m, 3H), 7.25-7.28 (m, 1H),6.52 (s, 2H), 4.66 (t, J=5.0 Hz, 2H), 4.55 (t, J=6.5 Hz, 2H), 4.41-4.46(m, 3H), 4.31-4.34 (m, 1H), 4.11-4.18 (m, 3H), 3.85-3.87 (m, 1H), 3.77(s, 3H), 3.43 (t, J=6.5 Hz, 1H), 3.12 (t, J=5.0 Hz, 4H), 2.54-2.63 (m,2H), 2.46 (t, J=6.0 Hz, 2H), 2.39 (t, J=5.0 Hz, 4H), 1.79 (t, J=5.5 Hz,2H), 1.69 (s, 2H).

Example 3295-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7),10,12-tetraen-6-one329 Example 329a (2Z)-3-(1-Benzothiophen-3-yl)prop-2-enoic Acid 329a

A suspension of benzo[b]thiophene-3-carbaldehyde (4.9 g, 30 mol),malonic acid (6.6 g, 60 mmol) and piperidine (1 mL) in 100 mL anhydrouspyridine was heated at 110° C. for overnight. The reaction mixture wascooled to room temperature and the solvent was removed in vacuo. Theresidue was taken up in 100 mL of water and 1 N hydrochloric acid wasadded to adjust the pH of this solution to ca. 3. The resultingsuspension was filtered and the yellow solid was collected, washed withwater (3×30 mL) dried in vacuo to give 329a as a yellow solid (5.5 g,89%). MS: [M+H]⁺ 205.

Example 329b 3-(1-Benzothiophen-3-yl)propanoic Acid 329b

A suspension of 329a (5.5 g, 27 mmol) and 10% Pd/C (600 mg) in 1:1methanol/ethyl acetate (100 mL) was hydrogenated in a Parr apparatus at50 psi for overnight. The mixture was filtered through a pad of Celiteand the filtrate was concentrated under reduced pressure to give crude329b as a brown solid (5.0 g, 90%), which was used without furtherpurification for the next step. MS: [M+H]⁺ 207. ¹H NMR (500 MHz, CDCl3)δ 2.81-2.84 (t, J=8.5, 2H), 3.18-3.21 (m, 2H), 7.16 (s, 1H), 7.34-7.41(m, 2H), 7.74-7.76 (d, 1H), 7.85-7.87 (d, 1H).

Example 329c 3-(1-Benzothiophen-3-yl)propanoyl Chloride 329c

Intermediate 329b (5.0 g, 24 mmol) in sulfurous dichloride (15 mL) washeated at 100° C. for 4 hours. The mixture was cooled to roomtemperature and the solvent was evaporated in vacuo. 30 mL methylenechloride was added to the residue and the resulting mixture wasevaporated under reduced pressure to give 329c as a brown solid (5.3 g,97%), which was used without further purification for the next step. MS:[M+H]⁺ 225.

Example 329d7-Thiatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6),9,11-tetraen-5-one 329d

To 329c (5.0 g, 22.3 mmol) in methylene chloride (50 mL) was addedanhydrous aluminum trichloride (5.9 g, 44.6 mmol). The mixture wasstirred at room temperature for overnight. The reaction solution wasevaporated in vacuo and the residue was purified by columnchromatography eluting with 20:1 methylene chloride/methanol to give329d as a yellow solid (2.3 g, 55%). MS: [M+H]⁺ 189. ¹H NMR (500 MHz,CDCl3) δ 3.05-3.07 (m, 2H), 3.21-3.23 (m, 2H), 7.45-7.52 (m, 2H),7.88-7.91 (m, 2H).

Example 329eN-[(5Z)-7-Thiatricyclo[6.4.0.0^(2,6)]dodeca-1(8),2(6),9,11-tetraen-5-ylidene]hydroxylamine329e

To a solution of NH₂OH.HCl (18.4 g, 266 mmol) in MeOH (600 mL) at 0° C.was slowly added CH₃COONa (21.8 g, 266 mmol). After stirring at 0° C.for 30 min, 329d (10 g, 53 mmol) was added. The reaction solution wasallowed to warm to room temperature and stirred for overnight. It wasthen evaporated in vacuo. 100 mL of water was added to the residue andthe resulting mixture was extracted with ethyl acetate (500 mL×3). Theorganic layers were combined, washed with brine (50 mL), and dried oversodium sulfate. The drying agent was removed by filtration and thefiltrate was concentrated under reduced pressure to give 329e as ayellow solid (10 g, 92%). MS: [M+H]⁺ 203.

Example 329f8-Thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7),10,12-tetraen-6-one329f

A solution of 329e (5 g, 25 mmol) in PPA (80 mL) was stirred at 150° C.in an oil bath for overnight. The reaction was cooled to roomtemperature and diluted with 150 mL of water/ice. The solid wascollected by filtration, washed with 3×50 mL of water and dried in avacuum oven under reduced pressure to afford the crude product, whichwas further purified by column chromatography eluting with 1:1 ethylacetate/petroleum ether to give 329f as a yellow solid (3 g, 60%). MS:[M+H]⁺ 204

Example 329g(2-Bromo-4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7),10,12-tetraen-5-yl}phenyl)methylAcetate 329g

A mixture of 329f (700 mg, 3.4 mmol), 197c (3.35 g, 10.2 mmol), XantPhos(200 mg, 0.34 mmol), Pd₂(dba)₃ (316 mg, 0.34 mmol) and Cs₂CO₃ (2.25 g,6.8 mmol) in dioxane (50 mL) was heated at 100° C. for 15 h under argonatmosphere. It was then filtered and evaporated in vacuo. The residuewas purified by column chromatography eluting with 1:3 ethylacetate/petroleum ether to give 329g as a white solid (500 mg, 33%). MS:[M+H]⁺ 448.

Example 329h[4-Fluoro-2-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)-6-{6-oxo-8-thia-5azatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7),10,12-tetraen-5-yl}phenyl]methyl329h

A sealed tube was charged with the mixture of 329g (300 mg, 0.66 mmol),1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-ylboronicacid 197f (690 mg, 1.32 mmol), Pd(dppf)Cl₂ (54 mg, 0.066 mmol), andNa₂CO₃ (141 mg, 1.32 mmol) in DMF (22 mL). The system was evacuated andthen refilled with N₂. And the reaction mixture was heated at 130° C. inmicrowave for 1 h. Then, the mixture was cooled to room temperature andfiltered. The filtrate was concentrated under reduced pressure and theresulting residue was purified by column chromatography eluting with15:1 methylene chloride/methanol to give 329h as a brown solid (300 mg,67%). MS: [M+H]⁺ 667.

At room temperature, to a solution of 329h (250 mg, 0.38 mol) inTHF/isopropanol/water (10 mL/10 mL/2 mL) was added LiOH (90 mg, 38 mmol)while stirring. This mixture was stirred for 2 h. Then, 20 mL water wasadded and resulting mixture was extracted with ethyl acetate (30 mL×3).The combined organic layer was dried with Na₂SO₄ and concentrated togive a yellow solid, which was further purified by prep-HPLC to afford329 as a brown solid (37 mg, 16%). MS: [M+H]⁺ 625. ¹H NMR (500 MHz,MEOD) δ 1.31 (s, 3H), 2.39 (s, 4H), 2.65-2.69 (m, 4H), 3.30-3.33 (m,2H), 3.68 (s, 3H), 4.11-4.16 (m, 1H), 4.24-4.30 (m, 1H), 4.50-4.56 (m,2H), 6.99 (d, 1H), 7.20 (d, 1H), 7.22 (d, 1H), 7.30 (s, 1H), 7.36-7.38(m, 1H), 7.47-7.54 (m, 2H), 7.89-7.95 (m, 2H), 7.97 (d, 1H), 8.53 (s,1H).

Example 3302-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one330 Example 330a tert-Butyl4-(6-Aminopyridazin-3-yl)piperazine-1-carboxylate 330a

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with 6-chloropyridazin-3-amine (2.58 g, 20 mmol) andN-Boc-piperazine (22.3 g, 120 mmol). The reaction mixture was heated at140° C. and stirred for 2 h. It was then cooled to room temperature andthe resulting solid was washed with ethyl acetate (100 mL), and theresulting residue was purified by flash column chromatography elutingwith 30:1 methylene chloride/methanol to afford 330a as a yellow solid(3.5 g, 60%). MS: [M+H]⁺ 280.

Example 330b tert-Butyl4-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridazin-3-yl)piperazine-1-carboxylate330b

Following Example 188c, 3,5-dibromo-1-methylpyridin-2(1H)-one (536 mg,2.0 mmol) and 330a (558 mg, 2.0 mmol) were reacted to give 330b as ayellow solid (560 mg, 60%). MS: [M+H]⁺ 467

Example 330c5-Bromo-1-methyl-3-(6-(piperazin-1-yl)pyridazin-3-ylamino)pyridin-2(1H)-one330c

Following Example 188d, 560 mg (1.2 mmol) of 330b was deprotected togive 330c as a yellow solid (440 mg, 99%). MS: [M+H]⁺ 367.

Example 330d5-Bromo-1-methyl-3-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridazin-3-ylamino)pyridin-2(1H)-one330d

Following Example 210a, 400 mg (1.1 mmol) of 330c was converted to 330das a yellow solid (312 mg, 68%). MS: [M+H]⁺ 421

Example 330e4-Fluoro-2-(1-methyl-5-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 330e

Following Example 210a, 207 mg of4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (0.43 mmol) and 180 mg of 330d (0.43 mmol) were reacted togive 330e as a yellow solid (156 mg, 51%). MS: [M+H]⁺ 697.

Following Example 210, 330e (150 mg 0.22 mmol) was hydrolyzed to give330 as a yellow solid (60 mg, 42%). LCMS: [M+H]⁺ 655. ¹H NMR (500 MHz,CDCl3) δ 8.67 (d, J=2.5, 1H), 7.77 (s, 1H), 7.48 (d, J=2.0, 1H), 7.12(dd, J=8.5, 1H), 6.98 (m, 3H), 6.86 (s, 1H), 4.69 (m, 4H), 4.51 (d,J=11, 1H), 4.20 (m, 5H), 3.86 (m, 1H), 3.71 (s, 3H), 3.56 (m, 5H), 2.60(m, 4H), 2.47 (m, 4H), 1.90 (s, 2H), 1.80 (s, 2H).

Example 331 2-(5-Fluoro-2-(hydroxymethyl)-3-(4-methyl-6-(6-(4-methylpiperazin-1-yl)pyridine-3-ylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)331 Example 331a5-Bromo-1-methyl-3-(6-(4-methylpiperazin-1-yl)pyridine-3-ylamino)pyrazin-2(1H)-one 331a

A mixture of 6-(4-methylpiperazin-1-yl)pyridin-3-amine (1 g, 5.2 mmol)prepared according to US 2009/0318448,3,5-dibromo-1-methylpyrazin-2(1H)-one (1.7 g, 6.2 mmol), and isopropanol(20 mL) was stirred at reflux for 16 h. After the reaction wascompleted, the solvent was removed to give 331a as a brown solid (500mg, 30%). MS: [M+H]⁺ 379.

Example 331b4-Fluoro-2-(4-methyl-6-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 331b

A sealed tube was charged with the mixture of 331a (400 mg, 1 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (578 mg, 1.2 mmol), Pd(dppf)Cl₂ (82 mg, 0.1 mmol),K₃PO₄.3H₂O (760 mg, 2 mmol), and NaOAc (164 mg, 2 mmol) in CH₃CN (10mL). The system was evacuated and then refilled with N₂ and the reactionmixture was heated at 110° C. for 2 h. The mixture was then cooled toroom temperature and filtered. The filtrate was concentrated underreduced pressure and the resulting residue was purified by flash columnchromatography eluting with 50:1 methylene chloride/methanol to afford331b as a yellow solid (100 mg, 14%). MS: [M+H]⁺ 655.

To the solution of 331b (100 mg, 0.15 mmol) in THF/isopropanol/water (2mL/2 mL/1 mL) was added LiOH (15 mg, 0.75 mmol). The reaction mixturewas stirred at 30° C. for 1 h. Then, 20 mL water was added and themixture was extracted with ethyl acetate (90 mL×3). The combined organiclayer was dried with Na₂SO₄ and concentrated to give yellow solid, whichwas purified by prep-HPLC to give 331 as a yellow solid (42 mg, 45%).MS: [M+H]⁺ 613. ¹H NMR (500 MHz, DMSO) δ 9.26 (s, 1H), 8.67 (d, J=2.5,1H), 8.35 (q, J=2.5, 1H), 7.44 (s, 1H), 7.32 (m, 2H), 6.82-6.80 (d, J=9,1H), 6.52 (s, 1H), 4.46-4.36 (m, 2H), 4.16-4.09 (m, 3H), 3.88-3.87 (m,1H), 3.52 (s, 3H), 3.40-3.34 (m, 5H), 2.60-2.57 (m, 2H), 2.51-2.45 (m,2H), 2.39-2.37 (m, 4H), 2.20 (s, 3H), 1.79-1.69 (m, 4H).

Example 3322-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methyl-2-oxopiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one332 Example 332a tert-Butyl 3-Oxopiperazine-1-carboxylate 332a

To a dry 100 mL one necked round bottom flask equipped with a stirringbar was added piperazin-2-one (5.0 g, 50 mmol), anhydrousdichloromethane (60 mL), and Et₃N (3.2 mL, 22.5 mmol) and the reactionmixture was stirred for 1 h at room temperature. The organic layer wasconcentrated under reduced pressure to afford 332a (10 g, 99%).

Example 332b tert-Butyl4-(6-Nitropyridin-3-yl)-3-oxopiperazine-1-carboxylate 332b

A microwave vial was charged with 332a (1.5 g, 7.5 mmol) in 30 mL ofanhydrous 1,4-dioxane, 5-bromo-2-nitropyridine (1.27 g, 6.25 mmol),diacetoxypalladium (71.8 mg, 0.32 mmol), Xantphos (278 mg, 0.48 mmol),and Cs₂CO₃ (2.04 g, 6.25 mmol). After three cycles of vacuum/argonflash, it was heated at 120° C. under microwave irradiation for 1.5 h.The reaction mixture was filtered and the filtrate was evaporated invacuum. The residue was purified by silica gel-column chromatographyeluting with 3:1 petroleum ether/ethyl acetate to afford 332b as ayellow solid (1.1 g, 54%). MS: [M+H]⁺ 323. ¹H NMR (500 MHz, CDCl₃) δ8.68 (d, J=2.5 Hz, 1H), 8.31 (d, J=9 Hz, 1H), 8.15 (m, 1H), 4.33 (s,2H), 3.91 (m, 4H).

Example 332c tert-Butyl4-(6-Aminopyridin-3-yl)-3-oxopiperazine-1-carboxylate 332c

To a solution of 332b (1.1 g, 3.4 mmol) in methanol (20 mL) was addedPd/C (10%) (250 mg). After three cycles of vacuum/H₂ flash, the mixturewas stirred under H₂ at room temperature for 10 h. The mixture wasfiltered and the filtrate was evaporated in vacuo to afford 332c (946mg, 95%), which was used for the next step without further purification.MS: [M+H]⁺ 293.

Example 332d tert-Butyl4-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)-3-oxopiperazine-1-carboxylate332d

A reaction vessel was charged with 332c (946 mg, 3.2 mmol) in 40 mL ofanhydrous 1,4-dioxane, 3,5-dibromo-1-methylpyridin-2(1H)-one (1.11 g,4.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.16 mmol),Xantphos (185 mg, 0.32 mmol), and Cs₂CO₃ (2.6 g, 8.0 mmol). After threecycles of vacuum/Argon flash, it was stirred at 110° C. for 4 h. Thereaction mixture was filtered and the filtrate was evaporated in vacuum.The crude was purified by silica-gel column chromatography eluting with50:1 methylene chloride/methanol to afford 332d as a yellow solid (706mg, 46%). MS: [M+H]⁺ 479.

Example 332e1-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)piperazin-2-one 332e

A 50-mL round-bottomed flask equipped with a magnetic stirrer and refluxcondenser was charged with HCl in 1,4-dioxane (20 mL) and 332d (706 mg,1.47 mmol). The mixture was stirred for at 65° C. for 6 h. It was thenconcentrated under reduced pressure to afford 332e as a yellow solid(500 mg, 90%). MS: [M+H]⁺ 379.

Example 332f1-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)-4-methylpiperazin-2-one332f

To a solution of1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)piperazin-2-one(332e) (500 mg, 1.32 mmol) in methanol (20 mL) was added Na(OAc)₃BH (2.0g, 13.2 mmol), formaldehyde (30% aq., 8 mL), and acetic acid (2.7 mL, 45mmol). The mixture was stirred for 4 h. The pH of the reaction mixturewas adjust to 11˜13 by adding NaOH (1M). It was then extracted withmethylene chloride three times. The combined organic exact was driedover anhydrous Na₂SO₄, filtered, and evaporated in vacuo. The residuewas purified by silica-gel column eluting with 50:1 methylenechloride/methanol to afford 332f as a gray solid (312 mg, 60%). MS:[M+H]⁺ 393. ¹H NMR (500 MHz, CDCl₃) δ 8.61 (d, J=2.5 Hz, 1H), 8.17 (d,J=2.5 Hz, 1H), 7.88 (s, 1H), 7.45 (dd, J=9 Hz, 1H), 6.92 (d, J=2.5 Hz,1H), 6.74 (d, J=9 Hz, 1H), 3.64 (m, 2H), 3.53 (s, 3H), 3.22 (s, 2H),2.74 (m, 2H), 2.35 (s, 3H).

Example 332g4-Fluoro-2-(1-methyl-5-(5-(4-methyl-2-oxopiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylacetate 332g

A reaction vessel was charged with the mixture of1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)-4-methylpiperazin-2-one(332f) (0.3 g, 0.76mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (0.37 g, 0.76 mmol), PdCl₂(dppf) (65 mg, 0.076 mmol), K₃PO₄(325 mg, 1.53 mmol), and NaOAc (125 mg, 1.53 mmol) in MeCN (15 mL) andwater (1 mL). It was then bubbled with argon for 15 min and heated at110° C. for 3 h. After evaporation of solvent in vacuo, the residue waspurified on silica-gel column eluting with 50:1 methylenechloride/methanol to afford 332g (0.4 g, 63%). MS: [M+H]⁺ 668.

A mixture of 332g (350 mg, 0.52 mmol) and LiOH hydrate (1.1 g, 26 mmol)in isopropanol (3 mL), THF (3 mL) and water (3 mL) was stirred at 30° C.for 1 h. The mixture was evaporated in vacuo, and the residue wasextracted with methylene chloride (30 mL×3). The combined extracts wereconcentrated under reduced pressure and the residue was purified onsilica gel column eluting with 50:1 methylene chloride/methanol toafford 332 as a yellow solid (120 mg, 32%). MS: [M+H]⁺ 626. ¹H NMR (500MHz, CDCl₃) δ 8.78 (d, J=2 Hz, 1H), 8.17 (d, J=2.5 Hz, 1H), 7.58 (dd,J=8.5 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 7.23 (s, 1H), 7.21 (s, 1H), 7.12(d, J=9 Hz, 1H), 6.73 (s, 1H), 4.53 (m, 2H), 4.22 (s, 2H), 4.03 (m, 1H),3.73 (s, 4H), 3.27 (s, 2H), 2.87 (m, 2H), 2.65 (m, 1H), 2.55 (m, 2H),2.43 (s, 3H), 1.89 (m, 2H), 1.79 (m, 2H).

Example 3332-(5-Fluoro-2-(methoxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one333

To a solution of2-(5-fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one197 (200 mg, 0.33 mmol) and K₂CO₃(135 mg, 0.99 mmol) in DMF (30 mL) wasadded the solution of iodomethane (70 mg, 0.50 mmol) in DMF (5 mL) atroom temperature. The reaction mixture was stirred for 1 h. It was thenfiltered and the residue was purified by prep-HPLC to afford 333 as ayellow solid (165 mg, 80%). MS: [M+H]⁺ 626. ¹H NMR (500 MHz, DMSO) δ8.59 (d, J=2.0, 1H), 8.49 (s, 1H), 7.97 (d, J=2.0, 1H), 7.44 (s, 1H),7.39 (s, 1H), 7.32 (m, 2H), 7.17 (m, 1H), 6.52 (s, 1H), 4.31 (s, 2H),4.14 (m, 3H), 3.88 (s, 1H), 3.56 (s, 3H), 3.54 (s, 4H), 3.44 (s, 4H),3.12 (s, 6H), 2.58 (m, 2H), 2.46 (s, 2H), 1.79 (s, 2H), 1.68 (s, 2H).

Example 334{4-Fluoro-2-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-6-{7-oxo-3,6-diazatetracyclo[9.2.1.0^(2,10)0.0^(3,8)]tetradeca-2(10),8-dien-6-yl}phenyl}methylAcetate 334 Example 334a 3-Chlorobicyclo[2.2.1]hept-2-ene-2-carbaldehyde334a

A 250-mL three-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged withanhydrous 1,2-dichloroethane (24 mL) and anhydrous DMF (9.12 g, 125mmol). The reaction mixture was cooled to 0° C., and phosphorusoxychloride (15.3 g, 100 mmol) was added over a period of 5 minutes,while maintaining the reaction temperature between 0 and 10° C. Thecooling bath was removed, and the reaction was stirred at roomtemperature for 30 minutes. A solution of bicyclo[2.2.1]heptan-2-one(5.50 g, 50.0 mmol) in 1,2-dichloroethane (10 mL) was added and theresulting mixture was heated at 80° C. for overnight. After this time,the reaction was poured into a solution of potassiummonohydrogenphosphate (43.5 g, 250 mmol) in water (200 mL) and stirredfor 15 minutes. The organic layer was separated and concentrated underreduced pressure. The residue was dissolved in methylene chloride (300mL) and washed with water (2×50 mL). The methylene chloride layer wasdried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography eluting with1:100 ethyl acetate/petroleum ether to give 334a as a yellow oil (2.2 g,28%). MS: [M+H]⁺ 157. ¹H NMR (500 MHz, CDCl3) δ 9.80 (s, 1H), 3.42 (s,1H), 3.07 (d, J=1.7 Hz, 1H), 1.95-1.77 (m, 2H), 1.67 (t, J=8.9 Hz, 1H),1.41-1.17 (m, 3H).

Example 334b (E)-Ethyl 3-(3-Chlorobicyclo[2.2.1]hept-2-en-2-yl)acrylate334b

To a solution of 334a (9.0 g, 57.7 mmol) in methylene chloride (250 mL)was added ethyl 2-(triphenyl-λ⁵-phosphanylidene)acetate (20 g, 57.7mmol). The mixture was stirred at room temperature for overnight. Afterreaction the reaction solution was evaporated in vacuo. The residue waspurified by column chromatography eluting with 1:100 ethylacetate/petroleum ether to give 334b as a yellow oil (6.0 g, 46%). MS:[M+H]⁺ 227.

Example 334c Ethyl3-Azatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-4-carboxylate 334c

To a solution of 334b (5.0 g, 22 mmol) in DMSO (30 mL) was added NaN₃(2.2 g, 33 mmol) and the mixture was heated at 105° C. for 6 hours.Water (13 mL) was added to reaction the mixture after cooling down toroom temperature, and resulting mixture was extracted with methylenechloride (50 mL×3). The organic phase was dried (Na₂SO₄) and evaporatedto dryness. The residue was purified by column chromatography elutingwith 20:1 methylene chloride/methanol to give 334c as a brown solid (2.7g, 60%). MS: [M+H]⁺ 206. ¹H NMR (500 MHz, CDCl3) δ 11.51 (s, 1H), 6.45(dd, 1H), 4.14-4.19 (m, 2H), 3.25 (d, 2H), 1.79-1.82 (m, 2H), 1.73 (d,1H), 1.22-1.25 (t, J=6.5, 3H), 0.89-0.91 (m, 2H).

Example 334d Ethyl3-(Cyanomethyl)-3-azatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-4-carboxylate334d

To a solution of 334c (3.0 g, 14.6 mmol) in anhydrous DMF (30 mL) wasadded NaH (880 mg, 22 mmol). The mixture was stirred at room temperaturefor 30 minutes. 2-Bromoacetonitrile (3.5 g, 29.3 mmol) was added and theresulting mixture was heated at 65° C. for 1 hour. It was then cooled toroom temperature and stirred for overnight. After reaction water (30 mL)was added and the reaction mixture was extracted with ethyl acetate(3×200 mL). The organic phase was evaporated to dryness. The residue waspurified by column chromatography eluting with 20:1 methylenechloride/methanol to give 334d as a brown solid (2.6 g, 72%). MS: [M+H]⁺245.

Example 334e Ethyl3-(2-Aminoethyl)-3-azatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-4-carboxylate334e

A suspension of 334d (4.0 g, 16 mmol) and Raney Ni (400 mg) in methanol(60 mL) was hydrogenated in a Parr apparatus at 50 psi for overnight.The mixture was filtered through a pad of Celite and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 20:1 methylene chloride/methanol to give334e as a yellow solid (2 g, 50%). MS: [M+H]⁺ 249.

Example 334f3,6-Diazatetracyclo[9.2.1.0^(2,10).0^(3,8)]tetradeca-2(10),8-dien-7-one334f

To a solution of ethyl3-(2-aminoethyl)-3-azatricyclo[5.2.1.0²⁶]deca-2(6),4-diene-4-carboxylate(334e) (1.8 g, 7.2 mmol) in ethanol (40 mL) was added sodium meth-oxide(2.5 g, 36 mmol). The mixture was heated at 65° C. for 12 hours. It wasthen cooled to room temperature. The solvent was evaporated to dryness.The residue was purified by column chromatography eluting with 20:1methylene chloride/methanol to give 334f as a brown solid (800 mg, 53%).MS: [M+H]⁺ 203.

Example 334g(2-Bromo-4-fluoro-6-{7-oxo-3,6-diazatetracyclo[9.2.1.0^(2,10).0^(3,8)]tetradeca-2(10),8-dien-6-yl}phenyl)methylAcetate 334g

Into a sealed tube was charged with 334f (800 mg, 4 mmol) and 197c (3.8g, 12 mmol) in dioxane (25 mL), and cesium carbonate (2.6 g, 8 mmol).After bubbling nitrogen through the resulting solution for 30 min,XantPhos (230 mg, 0.4 mmol) andtris(dibenzylideneacetone)-dipalladium(0) (362 mg, 0.4 mmol) were added,and the reaction mixture was heated at 100° C. for 4 h. After this timethe reaction was cooled to room temperature, and partitioned betweenethyl acetate (100 mL) and water (100 mL). The aqueous layer wasseparated and extracted with ethyl acetate (50 mL×3). The organic layerswere combined, washed with brine (20 mL×3), and dried over sodiumsulfate. The drying agent was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 1:5 ethyl acetate/petroleum ether to give334g as a brown solid (1.3 g, 72%). MS: [M+H]⁺ 447.

Example 334h(4-Fluoro-2-{7-oxo-3,6-diazatetracyclo[9.2.1.0^(2,10).0^(3,8)]tetradeca-2(10),8-dien-6-yl}-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylAcetate 334h

To a solution of 334g (450 mg, 1.0 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (770 mg, 3.0mmol) in dioxane (40 mL) was added PdCl₂(dppf) (82 mg, 0.1 mmol) andCH₃COOK (593 mg, 6 mmol). The mixture was stirred at 100° C. for 12 hunder argon atmosphere. After reaction the mixture was filtered andevaporated in vacuo. The residue was purified by column chromatographyeluting with 1:4 ethyl acetate/petroleum ether to give 334h as a brownsolid (400 mg, 80%). MS: [M+H]⁺ 495.

Example 334i{4-Fluoro-2-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-6-{7-oxo-3,6-diazatetracyclo[9.2.1.0^(2,10).0^(3,8)]tetradeca-2(10),8-dien-6-yl}phenyl}methylAcetate 334i

A sealed tube was charged with 334h (300 mg, 0.6 mmol), 188e (254 mg,0.6 mmol), Na₂CO₃ (129 mg, 1.2 mmol), PdCl₂(dppf) (50 mg, 0.06 mmol)suspended in DMF (20 mL), and H₂O (1 mL). The mixture was stirred at 80°C. for 5 hours. After reaction the mixture was partitioned between ethylacetate and water. The organic phase was washed with water (2×), driedover sodium sulfate and concentrated. The residue was purified byreverse phase Combi-flash eluting with 0.3% NH₄HCO₃ in 1:5 water/CH₃CNto give 334i as a brown solid (300 mg, 70%). MS: (M+H)⁺ 708.

At room temperature, to the solution of 334i (280 mg, 0.4 mol) inTHF/isopropanol/water (10 mL/10 mL/2 mL) was added LiOH (950 mg, 40mmol) while stirring. This mixture was stirred for 2 h. Then, 20 mLwater was added and resulting mixture was extracted with ethyl acetate(3×30 mL). The combined organic layer was dried with Na₂SO₄ andconcentrated to give a yellow solid, which was further purified byreverse phase Combi-flash eluting with 0.3% NH₄HCO₃ in 1:4 water/CH₃CNto give 334 as a white solid (160 mg, 67%). MS: [M+H]⁺ 666. ¹H NMR (500MHz, MEOD) δ 8.53 (s, 1H), 7.93 (d, 1H), 7.43 (d, 1H), 7.34 (s, 1H),7.20-7.22 (m, 2H), 7.04 (d, 1H), 6.67 (s 1H), 4.72-4.75 (t, J=6.5, 1H),4.63-4.66 (t, J=6, 2H), 4.47-4.56 (M, 2H), 4.21-4.39 (m, 3H), 3.98-4.06(m, 1H), 3.71 (s, 3H), 3.56-3.60 (m, 1H), 3.48 (s, 1H), 3.17-3.19 (t,J=4.5, 4H), 2.71 (s, 1H), 2.53-2.55 (t, J=5, 4H), 1.88-1.95 (m, 3H),1.67-1.69 (m, 1H), 1.04-1.17 (m, 2H).

Example 3352-(5-fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one335 Example 335a tert-Butyl5-(6-Nitropyridin-3-yl)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate335a

Following Example 188a, reaction of 404 mg of tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2 mmol) and 566 mg5-fluoro-2-nitropyridine (1.1 mmol) gave 335a as a yellow solid (234 mg,35%). MS: [M+H]⁺ 335. ¹H NMR (500 MHz, DMSO) δ 8.18 (d, J=9.0, 1H), 7.87(d, J=3.5, 1H), 7.06 (dd, J=9.0, 1H), 3.66 (s, 2H), 3.55 (s, 2H), 3.36(s, 2H), 3.18 (s, 2H), 3.05 (s, 2H), 1.39 (s, 9H).

Example 335b tert-Butyl5-(6-Aminopyridin-3-yl)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate335b

Following Example 188b, 234 mg of 335a (0.7 mmol) was reduced to give335b as a yellow solid (213 mg, 99%). MS: [M+H]⁺ 305

Example 335c tert-Butyl5-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridine-3-yl)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate335c

Following Example 188c, 3,5-dibromo-1-methylpyridin-2(1H)-one (212 mg,0.79 mmol) and 335b (200 mg, 0.66 mmol) were reacted to give 335c as ayellow solid (194 mg, 60%). MS: [M+H]⁺ 492

Example 335d5-Bromo-3-(5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino-1-methylpyridin-2(1H)-one335d

Following Example 188d, 194 mg (0.4 mmol) of 335c was deprotected togive 335d as a yellow solid (154 mg, 99%). MS: [M+H]⁺ 392

Example 335e5-Bromo-1-methyl-3-(5-(5-methyl-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)pyridin-2(1H)-one335e

Following Example 188e, 154 mg (0.4 mmol) of 335d was methylated to give335e as a yellow solid (119 mg, 75%). MS: [M+H]⁺ 404.

Example 335f4-Fluoro-2-(1-methyl-5-(5-(5-methyl-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 335f

Following Examples 148h, 142 mg of4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (0.29 mmol) and 119 mg of 335e (0.29 mmol) were reacted togive 335f as a yellow solid (100 mg, 51%). LCMS: [M+H]⁺ 680

Following Example 148, 100 mg of 335f (0.15 mmol), 335 was obtained as awhite solid (39 mg, 42%). ¹H NMR (500 MHz, CDCl3) δ 8.45 (d, J=2.0, 1H),7.70 (d, J=2.5, 1H), 7.67 (s, 1H), 7.42 (d, J=2.5, 1H), 7.17 (m, 1H),7.04 (dd, J=9.0, 1H), 6.95 (dd, J=6.0, 1H), 6.86 (s, 1H), 6.79 (d,J=9.0, 1H), 4.54 (d, J=11.0, 1H), 4.31 (m, 1H), 4.16 (m, 3H), 3.91 (m,1H), 3.70 (s, 3H), 3.27 (s, 2H), 3.18 (s, 2H), 2.99 (s, 2H), 2.83 (s,2H), 2.59 (m, 4H), 2.46 (m, 2H), 2.38 (s, 3H), 1.90 (s, 2H), 1.80 (s,2H).

Example 3362-(5-Fluoro-3-(5-(5-(3-(fluoromethyl)-4-methylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one336 Example 336a 1-tert-Butyl 2-Methyl4-benzylpiperazine-1,2-dicarboxylate 336a

To a dry 100 mL round bottom flask equipped with a stirring bar under N₂was added 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (5 g, 20.5mmol), anhydrous acetonitrile (60 mL), benzyl bromide (2.7 mL, 22.5mmol), and triethylamine (8.5 mL, 61.5 mmol). The reaction mixture washeated at 71° C. for 45 minutes and concentrated under reduced pressure.It was then diluted with methylene chloride and washed with water andbrine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude compound was purified byflash column chromato-graphy eluting with 8:1 petroleum either/ethylacetate to afford 336a (4.5 g, 66%). MS: [M+H]⁺ 335. ¹H NMR (500 MHz,CDCl₃) δ 7.28 (m, 5H), 4.60 (m, 1H), 3.78 (m, 4H), 3.57 (m, 1H), 3.43(m, 1H), 3.28 (m, 2H), 2.77 (m, 1H), 2.19 (m, 1H), 2.11 (m, 1H), 1.47(s, 5H), 1.42 (s, 4H).

Example 336b (4-Benzyl-1-methylpiperazin-2-yl)methanol 336b

To a solution of 336a (1 g, 2.99 mmol) in 100 mL of anhydroustetrahydrofuran was slowly added lithium aluminum hydride (342 mg, 8.98mmol) at 0° C. and the mixture was stirred for 30 min. Then, it wasrefluxed for 3 h and the reaction mixture was poured onto iceportionwise. The resulting mixture was filtered and the filtrate wasevaporated in vacuo. After addition of 100 mL brine to the residue, itwas extracted with methylene chloride (100 mL×3). The combined organiclayer was dried over Na₂SO₄, filtered, and concentrated to afford 336bas yellow oil (0.60 g, 91%). MS: [M+H]⁺ 221.

Example 336c 4-Benzyl-2-(fluoromethyl)-1-methylpiperazine 336c

To an ice-cooled solution of diethylaminosulfur trifluoride (10.8 mL,81.8 mmol) in methylene chloride under N₂ was added 336b (9.0 g, 40.9mmol) in methylene chloride dropwise. The yellow solution was stirred at0° C. for 1 h and then room temperature for 15 h. The reaction mixturewas then diluted with NaHCO₃, and the organic layer was separated anddried over Na₂SO₄. The crude product was purified on silica gel columnchromatography eluting with 50:1 methylene chloride/methanol to afford336c as a yellow oil (3.0 g, 33%). MS: [M+H]⁺ 223. ¹H NMR (500 MHz,DMSO) δ 7.28 (m, 5H), 4.50 (m, 0.5H), 4.43 (m, 1H), 4.35 (m, 0.5H), 3.45(s, 2H), 2.67 (m, 2H), 2.60 (m, 1H), 2.29 (m, 1H), 2.24 (s, 3H), 2.20(m, 1H), 2.11 (m, 1H), 1.94 (m, 1H).

Example 336d 2-(Fluoromethyl)-1-methylpiperazine 336d

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with 336c (3.0 g, 13.5 mmol), methanol (80 mL), andPd/C (10%) (300 mg). The reaction mixture was stirred at 25° C. under H₂for 15 h. After the reaction was finished, it was filtered andconcentrated to afford 336d as a yellow oil (1.6 g, 90%).

Example 336e 2-(Fluoromethyl)-1-methyl-4-(6-nitropyridin-3-yl)piperazine336e

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 336d(1.6 g, 12.1 mmol), 5-bromo-2-nitropyridine (3.7 g, 18.2 mmol), andcesium carbonate (9.9 g, 30.2 mmol). After bubbling nitrogen through theresulting solution for 30 min, Xantphos (700 mg, 0.12 mmol) andtris(dibenzylideneacetone)-dipalladium(0) (550 mg, 0.06 mmol) wereadded. After three cycles of vacuum/argon flash, the reaction mixturewas heated at reflux for 15 h. After this time the reaction was cooledto room temperature, filtered, and concentrated to afford a black solidas a crude product, which was further purified by column chromatographyeluting with 100:1 methylene chloride/methanol to afford 336e as ayellow solid (2.6 g, 76%). MS: [M+H]⁺ 255. ¹H NMR (500 MHz, MeOD) δ 8.20(m, 2H), 7.52 (dd, J=9, 1H), 4.72 (m, 0.5H), 4.64 (m, 1H), 4.56 (m,0.5H), 4.01 (m, 1H), 3.94 (m, 1H), 3.19 (m, 1H), 3.06 (m, 1H), 3.00 (m,1H), 2.50 (m, 2H), 2.46 (s, 3H).

Example 336f 5-(3-(Fluoromethyl)-4-methylpiperazin-1-yl)pyridin-2-amine336f

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with 336e (2.6 g, 10.2 mmol), methanol (50 mL), andPd/C (10%) (260 mg). The reaction mixture was stirred under H₂ for 15 h.After the reaction was finished, it was filtered and concentrated toafford 336f as a black oil, which was used in the next step withoutfurther purification. MS: [M+H]⁺ 225.

Example 336g5-Bromo-3-(5-(3-(fluoromethyl)-4-methylpiperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one336g

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 336f(crude, 14.1 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (4.5 g, 16.9mmol), and cesium carbonate (11.5 g, 35.2 mmol). After bubbling nitrogenthrough the resulting solution for 30 min, Xantphos (820 mg, 1.41 mmol)and tris(dibenzylideneacetone)dipalladium(0) (645 mg, 0.7 mmol) wereadded. After three cycles of vacuum/argon flash, the reaction mixturewas heated at reflux for 15 h. The reaction was cooled to roomtemperature, filtered and concentrated to afford a black solid, whichwas purified by column chromatography eluting with methylenechloride/methanol (from 100:1 to 50:1) to afford 336g as a yellow solid(3.1 g, 50%). MS: [M+H]⁺ 410.

Example 336h4-Fluoro-2-(5-(5-(3-(fluoromethyl)-4-methylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 336h

A reaction vessel was charged with a mixture of 336g (1 g, 2.4 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate 210d (1.3 g, 2.68 mmol), PdCl₂(dppf) (190 mg, 0.24 mmol), K₃PO₄(1 g, 4.8 mmol), and NaOAc (390 mg, 4.8 mmol) in MeCN (15 mL) and water(1.5 mL). It was bubbled with nitrogen for 30 min and then heated at110° C. for 3 h. The solvent was evaporated in vacuum and the residuewas purified on silica gel column chromatography eluting with 5:1methylene chloride/methanol to afford 336h (0.80 g, 45%). MS: [M+H]⁺686.

A mixture of 336h (750 mg, 1.09 mmol) and LiOH hydrate (2.3 g, 55 mmol)in isopropanol (10 mL), THF (10 mL), and water (10 mL) was stirred at30° C. for 1 h. The mixture was evaporated in vacuo, and the residue wasextracted with methylene chloride (30 mL×3). The combined extracts wereconcentrated under reduced pressure and the residue was purified onsilica gel column eluting with 50:1 methylene chloride/methanol toafford 336 as a yellow solid (700 mg, 93%). MS: [M+H]⁺ 644. ¹H NMR (500MHz, MeOD) δ 8.54 (d, J=2 Hz, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.42 (m, 1H),7.33 (m, 1H), 7.22 (s, 1H), 7.20 (s, 1H), 7.02 (m, 1H), 6.72 (s, 1H),4.46-4.69 (m, 4H), 4.20 (s, 3H), 4.02 (m, 1H), 3.70 (s, 3H), 3.49 (d,J=11.5 Hz, 1H), 3.42 (d, J=11.5 Hz, 1H), 2.94 (m, 1H), 2.85 (m, 1H),2.71 (m, 1H), 2.64 (m, 2H), 2.56 (m, 4H), 2.44 (s, 3H), 1.88 (m, 2H),1.79, (m, 2H).

Example 3376-[5-Fluoro-2-(hydroxymethyl)-3-{1-methyl-6-oxo-5-[(pyrimidin-4-yl)amino]-1,6-dihydropyridin-3-yl}phenyl]-3,6-diazatetracyclo[9.2.1.0^(2,10).0^(3,8)]tetradeca-2(10),8-dien-7-one337 Example 337a(4-Fluoro-2-{1-methyl-6-oxo-5-[(pyrimidin-4-yl)amino]-1,6-dihydro-pyridin-3-yl}-6-{7-oxo-3,6-diazatetracyclo[9.2.1.0^(2,10).0^(3,8)]tetradeca-2(10),8-dien-6-yl}phenyl)methylAcetate 337a

A sealed tube was charged with(2-bromo-4-fluoro-6-{7-oxo-3,6-diazatetracyclo-[9.2.1.0^(2,10).0^(3,8)]tetradeca-2(10),8-dien-6-yl}phenyl)methylacetate 334g (400 mg, 0.9 mmol),1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one109c (294 mg, 0.9 mmol), Na₂CO₃ (190 mg, 1.8 mmol), and PdCl₂(dppf) (73mg, 0.09 mmol) suspended in DMF (20 mL) and water (1 mL). The mixturewas stirred at 60° C. for 6 hours. It was then partitioned between waterand ethyl acetate. The organic phase was washed with water andevaporated to dryness. The residue was purified by column chromatographyeluting with 15:1 methylene chloride/methanol to give 337a as a brownsolid (300 mg, 58%). MS: [M+H]⁺ 569.

At room temperature, to the solution of 337a (270 mg, 0.47 mol) inTHF/isopropanol/water (10 mL/10 mL/2 mL) was added LiOH (1.1 g, 47 mmol)while stirring. This mixture was stirred for 2 h. Then, 20 mL water wasadded and the resulting mixture was extracted with ethyl acetate (30mL×3). The combined organic layer was dried with Na₂SO₄ and concentratedto get a yellow solid, which was further purified by reverse phaseCombi-flash eluting with 0.3% NH₄HCO₃ in 1:5 water/CH₃CN to give 337 asa white solid (138 mg, 48%). MS: [M+H]⁺ 527. ¹H NMR (500 MHz, MEOD) δ8.87 (s, 1H), 8.67 (s, 1H), 8.29 (d, 1H), 7.55 (s, 1H), 7.22-7.24 (m,2H), 7.10 (d, 1H), 6.68 (d, 1H), 4.48-4.55 (m, 2H), 4.18-4.40 (m, 3H),3.98-4.06 (m, 1H), 3.72 (s, 3H), 3.45-3.48 (m, 1H), 1.88-1.98 (m, 3H),1.67-1.69 (m, 1H), 1.30 (m, 1H), 1.12-1.17 (m, 1H), 1.02-1.07 (m, 1H).

Example 3382-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methyl-1,4-diazepan-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one338 Example 338a 1-Methyl-4-(6-nitropyridin-3-yl)-1,4-diazepane 338a

To a solution of 1-methyl-1,4-diazepane (1 g, 8.8 mmol) in DMSO (20 mL)were added K₂CO₃ (2.4 g, 18 mmol) and 5-bromo-2-nitropyridine (51-7)(1.78 g, 8.8 mmol). The mixture was stirred at 65° C. for overnight. Itwas allowed to cool to room temperature and poured into water. Theresulting solid was collected and dried under vacuum. The solid wasfurther purified by flash column eluting with 3:1 petroleum ether/ethylacetate and then methylene chloride to give 338a as a yellow solid (800mg, 69%). MS: [M+H]⁺ 236.

Example 338b 1-Methyl-4-(6-nitropyridin-3-yl)-1,4-diazepane 338b

A 500-mL bottle was purged with nitrogen and charged with 338a (0.8 g,3.4 mmol), 10% palladium on carbon (50% wet, 100 mg) and methanol (100mL). The bottle was evacuated, charged with hydrogen gas, and stirred atroom temperature for 16 h. The hydrogen was then evacuated and nitrogencharged to the bottle. The catalyst was removed by filtration through apad of Celite and the filtrate was concentrated under reduced pressureto afford 338b (0.6 g, crude). MS: [M+H]⁺ 207.

Example 338c5-Bromo-1-methyl-3-(5-(4-methyl-1,4-diazepan-1-yl)pyridin-2-ylamino)pyridine-2(1H)-one338c

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 338b (968 mg, 4.7 mmol),3,5-dibromo-1-methylpyridin-2(1H)-one (1.24 g, 4.7 mmol) and cesiumcarbonate (3.8 g, 12 mmol). After bubbling nitrogen through theresulting solution for 30 minutes, XantPhos (272 mg, 0.47 mmol) andtris(dibenzylideneacetone)dipalladium(0) (430 mg, 0.47 mmol) were added.The reaction mixture was heated at reflux for 3 h. After this time thereaction was cooled to room temperature, partitioned between ethylacetate (100 mL) and water (100 mL), and filtered. The aqueous layer wasseparated and extracted with ethyl acetate (2×50 mL). The organic layerswere combined, washed with brine (50 mL), and dried over sodium sulfate.The drying agent was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified on flashcolumn eluting with petroleum ether/ethyl acetate to afford 338c (918mg, 50%). MS: [M+H]⁺ 392.

Example 338d4-Fluoro-2-(1-methyl-5-(5-(4-methyl-1,4-diazepan-1-yl)pyridine-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 338d

A sealed tube was charged with the mixture of 338c (274 mg, 0.7 mmol),210d (337 mg, 0.7 mmol), Pd(dppf)Cl₂ (33 mg, 0.04 mmol), K₃PO₄.3H₂O (372mg, 1.4 mmol), and NaOAc (115 mg, 1.4 mmol) in CH₃CN (20 ml). The systemwas evacuated and then refilled with N₂. And the reaction mixture washeated at 110° C. under microwave irradiation for 3 h. The mixture wascooled to room temperature and filtered. The filtrate was concentratedunder reduced pressure and the resulting residue was purified by flashcolumn chromatography eluting with 30:1 methylene chloride/methanol toafford 338d as a yellow solid (120 mg, 43%). MS: [M+H]⁺ 668.

A solution of 338d (120 mg, 0.18 mmol) in propan-2-ol (10 mL),tetrahydrofuran (10 mL) and water (2 mL) was added LiOH (1.1 g, 57mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporatedand the residue was purified by prep-HPLC to afford 338 as a white solid(60 mg, 54%). MS: (M+H)⁺ 626. ¹H NMR (500 MHz, MeOD) δ 8.18 (s, 1H),7.62 (s, 1H), 7.16 (s, 1H), 7.06 (m, 3H), 6.88 (d, J=11.5, 2H), 6.59 (s,1H), 4.38 (m, 2H), 4.07 (m 3H), 3.87 (m, 1H), 3.57 (s, 3H), 3.42 (m,2H), 3.31 (m, 2H), 3.20 (s, 3H), 2.60 (m, 2H), 2.50 (m, 4H), 2.42 (m,2H), 1.75 (m, 6H).

Example 3395-[5-fluoro-2-(hydroxymethyl)-3-[1-methyl-5-({5-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]phenyl]-8-thia-4,5-diazatricyclo[7.4.0.0^(2,7)]-trideca-1(9),2(7),3(4)-trien-6-one339 Example 339a[4-Fluoro-2-(1-methyl-5-{[5-(4-(oxetan-3-yl)piperazin-1-yl)pyridine-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)-6-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7),3-trien-5-yl}phenyl]methylAcetate 339a

Following Example 210e, 150 mg (0.30 mmol) of(4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7),3-trine-5-yl}-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 341b was converted to 339a as a yellow solid (129 mg, 60%). MS:[M+H]⁺ 712

Following Example 148, 120 mg of 339a (0.17 mmol) was converted to 339as a white solid (56 mg, 50%). MS: [M+H]⁺ 670. ¹H NMR (500 MHz, DMSO) δ8.56 (d, J=3.0 Hz, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 7.88 (d, J=3.0 Hz,1H), 7.37 (m, 4H), 7.23 (d, J=9.5 Hz, 1H), 4.60 (t, J=10.0 Hz, 1H), 4.56(t, J=13.0 Hz, 2H), 4.46 (t, J=12.0 Hz, 2H), 4.28 (s, 2H), 3.58 (s, 3H),3.43 (m, 1H), 3.07 (t, J=9.0 Hz, 4H) 2.93 (s, 2H), 2.85 (s, 2H), 2.38(t, J=9.0 Hz, 4H), 1.87 (m, 4H).

Example 3402-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-ylpyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydro-6,9-methanopyrazino[1,2-a]indol-1(2H)-one340 Example 340a{4-Fluoro-2-[1-methyl-5-({5-[4-methylpiperazin-1-yl]pyridin-2yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-6-{7-oxo-3,6-diazatetracyclo[9.2.1.0^(2,10).0^(3,8)]tetradeca-2(10),8-dien-6-yl}phenyl}methylAcetate 340a

A microwave vial equipped with a magnetic stirrer was charged with(2-bromo-4-fluoro-6-{7-oxo-3,6-diazatetracyclo[9.2.1.0^(2,10).0^(3,8)]tetradeca-2(10),8-dien-6-yl}phenyl)methylacetate 334g (293 mg, 0.65 mmol),1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridine-2-ylamino)-6-oxo-1,6-dihydropyridin-3-ylboronicacid 197f (450 mg, 1.3 mmol), PdCl₂(dppf) (54 mg, 0.065 mmol), 2.0 MNa₂CO₃ (2.0 equiv), and 1,2-dimethoxyethane (18 mL). After three cyclesof vacuum/argon flash, the mixture was heated at 130° C. under microwaveirradiation for 0.5 h. It was then filtered and the filtrate wasevaporated in vacuo. The residue was purified on flash columnchromatography eluting with 10:1 dichloromethane/methanol to afford 340aas a brown solid (130 mg, 33%). LCMS: [M+H]⁺ 666

A mixture of 340a (130 mg, 0.20 mmol) and LiOH (470 mg, 20.0 mmol) inisopropanol/THF (1:1, 10 mL) and water (3 mL) was stirred at 30° C. for2 h. The mixture was evaporated in vacuo and the residue was extractedwith ethyl acetate (30 mL×2). The combined ethyl acetate extract wasconcentrated under reduced pressure and the residue was purified withprep-HPLC to afford 340 (50 mg, 41%). LCMS: [M+H]⁺ 624. ¹H NMR (500 MHz,MEOD) δ 8.54 (s, 1H), 7.93 (s, 1H), 7.41-7.43 (m, 1H), 7.34 (s, 1H),7.20-7.22 (m, 2H), 7.02-7.04 (d, J=9.0 Hz, 1H), 6.67-6.68 (d, J=3.0 Hz,1H), 4.46-4.55 (m, 2H), 4.18-4.38 (m, 3H), 3.98-4.06 (m, 1H), 3.71 (s,3H), 3.46-3.48 (m, 1H), 3.14-3.18 (m, 4H), 2.62-2.64 (t, J=4.5 Hz, 4H),2.36 (s, 3H), 1.88-1.95 (m, 3H), 1.67-1.69 (m, 1H), 1.01-1.30 (m, 2H).

Example 3415-[5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-8-thia-4,5-diazatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7),3-trien-6-one341 Example 341a(2-Bromo-4-fluoro-6-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7),3-trien-5-yl}phenyl)methylacetate 341a

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with8-thia-4,5-diazatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7),3-trien-6-one(1 g, 4.85 mmol), 2,6-dibromo-4-fluorobenzyl acetate 197c (4.8 g, 14.6mmol), copper(I) iodide (553 mg, 2.9 mmol),N¹,N²-dimethylethane-1,2-diamine (512 mg, 5.82 mmol), Cs₂CO₃ (3.2 g, 9.7mmol), and 1,4-dioxane (50 mL). The system was evacuated and thenrefilled with N₂. A reflux condenser was attached to the flask, and thereaction mixture was heated at 100° C. for 16 h. It was then cooled toroom temperature and filtered. The filtrate was concentrated underreduced pressure and the resulting residue was purified by flash columnchromatography eluting with 5:1 petroleum ether/ethyl acetate to afford341a as a yellow solid (437 mg, 20%). MS: [M+H]⁺ 451.

Example 341b(4-Fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7),3-trine-5-yl}-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylacetate 341b

Following Example 210d, 341a (400 mg 0.88 mmol) was converted to 341b asa yellow solid (353 mg, 80%). MS: [M+H]⁺ 499

Example 341c[4-Fluoro-2-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)-6-{6-oxo-8-thia-4,5-diazatricyclo-[7.4.0.0^(2,7)]trideca-1(9),2(7),3-trien-5-yl}phenyl]methylAcetate 341c

Following Example 210a, 180 mg (0.36 mmol) of 341b was converted to 341cas a yellow solid (120 mg, 50%). MS: [M+H]⁺ 670

Following Example 148, 120 mg of 341c (0.18 mmol) was converted to 341as a white solid (46 mg, 41%). MS: [M+H]⁺ 628. ¹H NMR (500 MHz, CDCl3) δ8.58 (d, J=2.5, 1H), 8.26 (s, 1H), 7.95 (d, J=3.0, 1H), 7.77 (s, 1H),7.45 (d, J=2.0, 1H), 7.31 (m, 1H), 7.25 (m, 1H), 7.11 (dd, J=8.0, 1H),6.82 (d, J=9.0, 1H), 4.31 (s, 1H), 4.01 (s, 1H), 3.71 (s, 3H), 3.15 (t,J=4.5, 4H), 2.99 (t, J=5.0, 2H), 2.87 (t, J=5.5, 2H), 2.60 (t, J=5.0,4H), 2.37 (s, 3H), 1.99 (s, 4H).

Example 3422-(5-Fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(6-(4-methylpiperazin-1-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one342 Example 342a 6-(4-Methylpiperazin-1-yl)pyridazin-3-amine 342a

A sealed tube equipped with a magnetic stirrer was charged with6-chloro-pyridazin-3-amine (1.3 g, 10 mmol) and 1-methylpiperazine (15mL). The reaction mixture was heated at 170° C. for 3 h. It was thencooled to room temperature and concentrated under reduced pressure. Theresulting residue was washed with CH₃CN (20 mL) to afford 342a as ayellow solid (1.5 g, 78%). MS: [M+H]⁺ 194. ¹H NMR (500 MHz, DMSO) δ 7.12(d, J=9.0 Hz, 1H), 6.74 (d, J=9.0 Hz, 1H), 5.72 (s, 2H), 3.27 (t, J=4.5Hz, 4H), 2.40 (t, J=4.5 Hz, 4H), 2.20 (s, 3H).

Example 342b5-Bromo-1-methyl-3-(6-(4-methylpiperazin-1-yl)pyridazin-3-ylamino)-pyridin-2(1H)-one342b

Following Example 188c, 342a (580 mg, 3.0 mmol) was converted to 342b asa yellow solid (920 mg, 80%). MS: [M+H]⁺ 381

Example 342c4-Fluoro-2-(1-methyl-5-(6-(4-methylpiperazin-1-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzylAcetate 342c

Following Example 188f, 482 mg of 342b (1.0 mmol) and 379 mg of5-bromo-1-methyl-3-(6-(4-methylpiperazin-1-yl)pyridazin-3-ylamino)pyridin-2(1H)-one(1.0 mmol) were reacted to give 342c as a yellow solid (261 mg, 40%).MS: [M+H]⁺ 655.

Following Example 188, 342c (150 mg 0.23 mmol) was converted to 342 as awhite solid (73 mg, 52%). LCMS: [M+H]⁺ 613. ¹H NMR (500 MHz, CDCl₃) δ8.68 (d, J=2.5 Hz, 1H), 7.76 (s, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.12 (dd,J=9.0 Hz, 1H), 7.0 (m, 2H), 6.90 (dd, J=9.0 Hz, 1H), 6.86 (s, 1H), 4.50(dd, J=11.0 Hz, 1H), 4.27 (m, 2H), 4.16 (m, 3H), 3.88 (m, 1H), 3.71 (s,3H), 3.54 (m, 4H), 2.58 (m, 7H), 2.35 (s, 3H), 1.90 (m, 2H), 1.71 (m,2H).

Example 901 Biochemical Btk Assay

A generalized procedure for a standard biochemical Btk Kinase Assay thatcan be used to test Formula I compounds is as follows. A master mixminus Btk enzyme is prepared containing 1× Cell Signaling kinase buffer(25 mM Tris-HCl, pH 7.5, 5 mM beta-glycerophosphate, 2 mMdithiothreitol, 0.1 mM Na₃VO₄, 10 mM MgCl₂), 0.5 μM Promega PTKBiotinylated peptide substrate 2, and 0.01% BSA. A master mix plus Btkenzyme is prepared containing 1× Cell Signaling kinase buffer, 0.5 μMPTK Biotinylated peptide substrate 2, 0.01% BSA, and 100 ng/well (0.06mU/well) Btk enzyme. Btk enzyme is prepared as follows: full lengthhuman wildtype Btk (accession number NM-000061) with a C-terminal V5 and6×His tag was subcloned into pFastBac vector for making baculoviruscarrying this epitope-tagged Btk. Generation of baculovirus is donebased on Invitrogen's instructions detailed in its published protocol“Bac-to-Bac Baculovirus Expression Systems” (Cat. Nos. 10359-016 and10608-016). Passage 3 virus is used to infect Sf9 cells to overexpressthe recombinant Btk protein. The Btk protein is then purified tohomogeneity using Ni-NTA column. The purity of the final proteinpreparation is greater than 95% based on the sensitive Sypro-Rubystaining. A solution of 200 μM ATP is prepared in water and adjusted topH7.4 with 1N NaOH. A quantity of 1.25 μL of compounds in 5% DMSO istransferred to a 96-well ½ area Costar polystyrene plate. Compounds aretested singly and with an 11-point dose-responsive curve (startingconcentration is 10 μM; 1:2 dilution). A quantity of 18.75 μL of mastermix minus enzyme (as a negative control) and master mix plus enzyme istransferred to appropriate wells in 96-well ½ area costar polystyreneplate. 5 μL of 200 μM ATP is added to that mixture in the 96-well ½ areaCostar polystyrene plate for final ATP concentration of 40 μM. Thereaction is allowed to incubate for 1 hour at room temperature. Thereaction is stopped with Perkin Elmer 1× detection buffer containing 30mM EDTA, 20 nM SA-APC, and 1 nM PT66 Ab. The plate is read usingtime-resolved fluorescence with a Perkin Elmer Envision using excitationfilter 330 nm, emission filter 665 nm, and 2^(nd) emission filter 615nm. IC₅₀ values are subsequently calculated. Alternatively, theLanthascreen assay can be used to evaluate Btk activity throughquantification of its phosphorylated peptide product. The FRET(Fluorescence Resonance Energy Transfer) that occurs between thefluorescein on the peptide product and the terbium on the detectionantibody decreases with the addition of inhibitors of Btk that reducethe phosphorylation of the peptide. In a final reaction volume of 25 uL,Btk (h) (0.1 ng/25 ul reaction) is incubated with 50 mM Hepes pH 7.5, 10mM MgCl2, 2 mM MnCl₂, 2 mM DTT, 0.2 mM NaVO4, 0.01% BSA, and 0.4 uMfluorescein poly-GAT. The reaction is initiated by the addition of ATPto 25 uM (Km of ATP). After incubation for 60 minutes at roomtemperature, the reaction is stopped by the addition of a finalconcentration of 2 nM Tb-PY20 detection antibody in 60 mM EDTA for 30minutes at room temperature. Detection is determined on a Perkin ElmerEnvision with 340 nM excitation and emission at 495 nm and 520 nm.Exemplary Btk inhibition IC50 values are in Tables 1, 2, and 3.

Example 902 Ramos Cell Btk Assay

Another generalized procedure for a standard cellular Btk Kinase Assaythat can be used to test Formula I compounds is as follows. Ramos cellsare incubated at a density of 0.5×10⁷ cells/ml in the presence of testcompound for 1 hr at 37° C. Cells are then stimulated by incubating with10 μg/ml anti-human IgM F(ab)₂ for 5 minutes at 37° C. Cells arepelleted, lysed, and a protein assay is performed on the cleared lysate.Equal protein amounts of each sample are subject to SDS-PAGE and westernblotting with either anti-phosphoBtk(Tyr223) antibody (Cell SignalingTechnology #3531; Epitomics, cat. #2207-1) or phosphoBtk(Tyr551)antibody (BD Transduction Labs #558034) to assess Btkautophosphorylation or an anti-Btk antibody (BD Transduction Labs#611116) to control for total amounts of Btk in each lysate.

Example 903 B-Cell Proliferation Assay

A generalized procedure for a standard cellular B-cell proliferationassay that can be used to test Formula I compounds is as follows.B-cells are purified from spleens of 8-16 week old Balb/c mice using aB-cell isolation kit (Miltenyi Biotech, Cat #130-090-862). Testingcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic B-cells for 30 min prior to addition of 10 μg/ml of ananti-mouse IgM antibody (Southern Biotechnology Associates Cat #1022-01)in a final volume of 100 μl. Following 24 hr incubation, 1 μCi³H-thymidine is added and plates are incubated an additional 36 hr priorto harvest using the manufacturer's protocol for SPA[³H] thymidineuptake assay system (Amersham Biosciences #RPNQ 0130). SPA-bead basedfluorescence is counted in a microbeta counter (Wallace Triplex 1450,Perkin Elmer).

Example 904 T Cell Proliferation Assay

A generalized procedure for a standard T cell proliferation assay thatcan be used to test Formula I compounds is as follows. T cells arepurified from spleens of 8-16 week old Balb/c mice using a Pan T cellisolation kit (Miltenyi Biotech, Cat #130-090-861). Testing compoundsare diluted in 0.25% DMSO and incubated with 2.5×10⁵ purified mousesplenic T cells in a final volume of 100 μl in flat clear bottom platesprecoated for 90 min at 37° C. with 10 μg/ml each of anti-CD3 (BD#553057) and anti-CD28 (BD #553294) antibodies. Following 24 hrincubation, 1 μCi ³H-thymidine is added and plates incubated anadditional 36 hr prior to harvest using the manufacturer's protocol forSPA[³H] thymidine uptake assay system (Amersham Biosciences # RPNQ0130). SPA-bead based fluorescence was counted in a microbeta counter(Wallace Triplex 1450, Perkin Elmer).

Example 905 CD86 Inhibition Assay

A generalized procedure for a standard assay for the inhibition of Bcell activity that can be used to test Formula I compounds is asfollows. Total mouse splenocytes are purified from spleens of 8-16 weekold Balb/c mice by red blood cell lysis (BD Pharmingen #555899). Testingcompounds are diluted to 0.5% DMSO and incubated with 1.25×10⁶splenocytes in a final volume of 200 μl in flat clear bottom plates(Falcon 353072) for 60 min at 37° C. Cells are then stimulated with theaddition of 15 μg/ml IgM (Jackson ImmunoResearch 115-006-020), andincubated for 24 hr at 37° C., 5% CO₂. Following the 24 hr incubation,cells are transferred to conical bottom clear 96-well plates andpelleted by centrifugation at 1200×g×5 min. Cells are preblocked byCD16/CD32 (BD Pharmingen #553142), followed by triple staining withCD19-FITC (BD Pharmingen #553785), CD86-PE (BD Pharmingen #553692), and7AAD (BD Pharmingen #51-68981E). Cells are sorted on a BD FACSCaliburand gated on the CD19⁺/7AAD⁻ population. The levels of CD86 surfaceexpression on the gated population is measured versus test compoundconcentration. Exemplary results are in Table 4.

TABLE 4 CD86 inhibition Compound EC₅₀ (mM) 105 0.064 110 0.022 113 0.021114 0.188 115 0.078 197 0.022 210 0.010 211 0.009 212 0.009 273 0.003277 0.028 284 0.006 285 0.011 286 0.004 289 0.010 290 0.010 296 0.001299 0.009 300 0.009 308 0.063 311 0.030 313 0.006 318 0.018 319 0.016321 0.044

Example 906 B-ALL Cell Survival Assay

The following is a procedure for a standard B-ALL (acute lymphoblasticleukemia) cell survival study using an XTT readout to measure the numberof viable cells. This assay can be used to test Formula I compounds fortheir ability to inhibit the survival of B-ALL cells in culture. Onehuman B-cell acute lymphoblastic leukemia line that can be used isSUP-B15, a human Pre-B-cell ALL line that is available from the ATCC.

SUP-B15 pre-B-ALL cells are plated in multiple 96-well microtiter platesin 100 μl of Iscove's media+20% FBS at a concentration of 5×10⁵cells/ml. Test compounds are then added with a final conc. of 0.4% DMSO.Cells are incubated at 37° C. with 5% CO₂ for up to 3 days. After 3 dayscells are split 1:3 into fresh 96-well plates containing the testcompound and allowed to grow up to an additional 3 days. After each 24 hperiod, 50 ul of an XTT solution is added to one of the replicate96-well plates and absorbance readings are taken at 2, 4 and 20 hoursfollowing manufacturer's directions. The reading taken with an OD forDMSO only treated cells within the linear range of the assay (0.5-1.5)is then taken and the percentage of viable cells in the compound treatedwells are measured versus the DMSO only treated cells.

Example 907 CD69 Whole Blood Assay

Human blood is obtained from healthy volunteers, with the followingrestrictions: 1 week drug-free, non-smokers. Blood (approximately 20 mlsto test 8 compounds) is collected by venipuncture into Vacutainer®(Becton, Dickinson and Co.) tubes with sodium heparin.

Solutions of Formula I compounds at 10 mM in DMSO are diluted 1:10 in100% DMSO, then are diluted by three-fold serial dilutions in 100% DMSOfor a ten point dose-response curve. The compounds are further diluted1:10 in PBS and then an aliquot of 5.5 μl of each compound is added induplicate to a 2 ml 96-well plate; 5.5 μl of 10% DMSO in PBS is added ascontrol and no-stimulus wells. Human whole blood—HWB (100 μl) is addedto each well. After mixing the plates are incubated at 37° C., 5% CO₂,100% humidity for 30 minutes. Goat F(ab′)2 anti-human IgM (10 μl of a500 μg/ml solution, 50 μg/ml final) is added to each well (except theno-stimulus wells) with mixing and the plates are incubated for anadditional 20 hours. At the end of the 20 hour incubation, samples areincubated with fluorescent labeled antibodies for 30 minutes, at 37° C.,5% CO₂, 100% humidity. Include induced control, unstained and singlestains for compensation adjustments and initial voltage settings.Samples are then lysed with PharM Lyse™ (BD Biosciences Pharmingen)according to the manufacturer's instructions. Samples are thentransferred to a 96 well plate suitable to be run on the BD BiosciencesHTS 96 well system on the LSRII machine. Data acquired and MeanFluorescence Intensity values were obtained using BD Biosciences DIVASoftware. Results are initially analyzed by FACS analysis software (FlowJo). The IC50 for test compounds is defined as the concentration whichdecreases by 50% the percent positive of CD69 cells that are also CD20positive stimulated by anti-IgM (average of 8 control wells, aftersubtraction of the average of 8 wells for the no-stimulus background).The IC50 values are calculated by Prism version 5, using a nonlinearregression curve fit.

Exemplary IC50 values of selected compounds from Tables 1, 2, and 3 inthe CD69 Whole Blood Assay include:

IC50 Compound No. (micromolar) 105 0.088 197 0.023 304 0.035 311 0.044339 0.053 341 0.024 322 0.053 323 0.024

We claim:
 1. A compound selected from Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein: R¹ is H, D, F, Cl, CN, NH₂, NHCH₃, —N(CH₃)₂, —OH,—OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, heteroaryl selected from imidazolyl andpyrazolyl, heterocyclyl selected from oxetanyl and azetidinyl, and C₁-C₃alkyl; R², R³ and R⁴ are independently selected from H, D, F, Cl, —NH₂,—NHCH₃, —N(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH, and C₁-C₃ alkyl; R⁵is optionally substituted C₆-C₂₀ aryl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₁-C₂₀ heteroaryl, —(C₆-C₂₀ aryl)-(C₂-C₂₀ heterocyclyl),—(C₁-C₂₀ heteroaryl)-(C₂-C₂₀ heterocyclyl), —(C₁-C₂₀ heteroaryl)-(C₁-C₆alkyl), or —(C₁-C₂₀ heteroaryl)-C(═O)—(C₂-C₂₀ heterocyclyl); R⁶ is H, F,—NH₂, —OH, or optionally substituted C₁-C₃ alkyl; X is S, S(═O), S(═O)₂,N, NR⁶, O, or CR⁷; R⁷ is independently selected from H, D, F, Cl, —CH₃,—CH₂CH₃, —CN, —CH₂F, —CHF₂, —CF₃, —NH₂, —OH, and —OCH₃; Y¹ and Y² areindependently selected from CR⁶ and N; Z¹, Z², Z³, and Z⁴ areindependently selected from C, CR⁷, and N; Z⁵ is selected from —C(R³)₂—,—C(═O)—; one of Z¹ and Z², or X and Z¹, where X is not S, S(═O), orS(═O)₂, forms a five-, six-, or seven-membered aryl, carbocyclyl,heterocyclyl or heteroaryl ring; where alkyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl are optionally substituted with one or more groupsindependently selected from D, F, Cl, Br, I, —CH₃, —CH₂CH₃,—CH₂CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂,—C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃, —CH₂OP(O)(OH)₂, —CN, —CH₂F, —CHF₂, —CF₃,—CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃,—CON(CH₃)₂, —C(CH₃)₂CONH₂, —NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃,—N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃,—CH₂OCH₃, —S(O)₂CH₃, cyclopropyl, azetidinyl, 1-methylazetidin-3-yl)oxy,N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, oxetanyl, andmorpholino.
 2. The compound of claim 1 selected from Formulas Ia-c:


3. The compound of claim 1 selected from Formulas Id-f:


4. The compound of claim 1 selected from Formulas Ig-n:


5. The compound of claim 1 selected from Formulas Io-t:


6. The compound of claim 1 where Z¹ and Z² forms a five-, six-, orseven-membered aryl, carbocyclyl, heterocyclyl or heteroaryl ring, andselected from Formulas Iaa-ap:


7. The compound of claim 1 where X and Z′, and X is not S, forms afive-, six-, or seven-membered aryl, carbocyclyl, heterocyclyl orheteroaryl ring, and selected from Formulas Iaq-bf:


8. The compound of claim 1 wherein R¹, R², R³, and R⁴ are each H.
 9. Thecompound of claim 1 wherein R¹ is selected from F, —CH₃, —CH₂F, —CHF₂,and —CF₃.
 10. The compound of claim 1 wherein R is —CH₂OH.
 11. Thecompound of claim 1 wherein R³ is F.
 12. The compound of claim 1 whereinR¹ is —CH₂OH, R² and R⁴ are each H, and R³ is F.
 13. The compound ofclaim 1 wherein R⁵ is optionally substituted C₆-C₂₀ aryl selected fromphenyl and naphthyl.
 14. The compound of claim 1 wherein R⁵ isoptionally substituted C₃-C₁₂ carbocyclyl selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
 15. The compoundof claim 1 wherein R⁵ is optionally substituted C₂-C₂₀ heterocyclylselected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl,piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl.
 16. Thecompound of claim 1 wherein R⁵ is optionally substituted C₁-C₂₀heteroaryl selected from pyrazolyl, pyridinyl, pyrimidinyl,5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl,5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl,6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl, and1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-yl.
 17. The compound ofclaim 1 wherein R⁵ is substituted with one or more groups selected fromF, Cl, —CH₃, cyclopropyl, azetidinyl, oxetanyl, and morpholino.
 18. Thecompound of claim 1 wherein R⁵ is selected from the structures:

where the wavy line indicates the site of attachment.
 19. The compoundof claim 1 wherein R⁶ is H.
 20. The compound of claim 1 wherein X is S.21. The compound of claim 1 wherein X is N.
 22. The compound of claim 1wherein X is CR⁷.
 23. The compound of claim 1 wherein Y¹ is CR⁶ and Y²is N.
 24. The compound of claim 1 wherein Y¹ is N and Y² is CR⁶.
 25. Thecompound of claim 1 wherein Y¹ and Y² are each CR⁶.
 26. A pharmaceuticalcomposition comprised of a compound of claim 1 and a pharmaceuticallyacceptable carrier, glidant, diluent, or excipient.
 27. Thepharmaceutical composition of to claim 1, further comprising a secondtherapeutic agent.